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URTICARIA AND ANGIOEDEMA

  1. OVERVIEW

Urticaria is characterized by wheals surrounded by an area of redness that is typically very pruritic. Individual hives can last as briefly as 30 minutes to as long as 36 hours. They can be as small as a millimeter or a few centimeters in diameter (giant urticaria). They blanch with pressure as the dilated blood vessels are compressed, which also accounts for the central pallor of the wheal. The dilated blood vessels and increased permeability that characterize urticaria are present in the superfcial dermis and involves the venular plexus in that location. Angioedema can be caused by the same pathogenic mechanisms as urticaria but the pathology is in the deep dermis and subcutaneous tissue and swelling is the major manifestation. The overlying skin may be erythematous or normal. There is less pruritus but there may be pain or burning.

Urticaria has been described since the time of Hippocrate (460-370 BC) and since ancient times, Eastern medicine has described metaphor for various causes that have symptoms similar to urticaria. The term “urticaria” is derived from the Latin word “urtica” meaning nettle, which is a wild, flowering, wind-pollinated tree, with hairs containing phocmic acid on trunk and leaves which cause a itchy and painful contact reaction

Urticaria and angioedema are common. 15-25 percent of the world’s popullation reported having experienced urticaria. Urticaria can occur in any age group, but there is a bimodal age distribution in patients aged birth to 9 years and 30–40 years.

Urticaria and angioedema are divided into two types: acute and chronic. Urticaria/angioedema is considered to be acute if it lasts less than 6 weeks; most acute episodes are due to adverse reactions to medications or foods and in children, to viral illnesses. Episodes of urticaria/angioedema persisting beyond 6 weeks are considered chronic and are divided into two major subgroups: (1) chronic autoimmune urticaria (45%) and (2) chronic idiopathic urticaria (55%) with a combined incidence in the general population of 0.5%. Physically induced urticaria/angioedema is not included in the definition. Various types of physical urticaria/angioedema may last for years, but the individual lesions last fewer than 2 hours (except delayed pressure urticaria) and are intermittent. Whereas 85% of children experience urticaria in the absence of angioedema, 40% of adult patients with urticaria also experience angioedema.

Approximately 50% of patients with chronic urticaria (with or without angioedema) are free of lesions within 1 year, 65% within 3 years, and 85% within 5 years; fewer than 5% have lesions that last for more than 10 years.

  1. PATHOGENESIS

2.1 Mast cell and histamine release

The mast cell is the major effector cell in most forms of urticaria and angioedema, although other cell types undoubtedly contribute. Cutaneous mast cells adhere to fbronectin and laminin through the very late activation (VLA) β1 integrins VLA-3, VLA-4, and VLA-5 and to vitronectin through the αvβ3 integrin. Cutaneous mast cells, but not those from other sites, release histamine in response to compound 48/80, C5a, morphine, and codeine. The neuropeptides substance P (SP), vasoactive intestinal peptide (VIP), and somatostatin, (but not neurotensin, neurokinins A and B, bradykinin, or calcitonin gene-related peptide), activate mast cells for histamine secretion. Not all potential biologic products are produced when cutaneous mast cells are stimulated. For example, SP releases histamine from cutaneous mast cells above 10−6 M but does not generate prostaglandin D2 (PGD2). Vascular permeability in skin is produced predominantly by H1 histamine receptors (85%); H2 histamine receptors account for the remaining 15%.

The current hypothesis regarding cellular infltration that follows mast cell degranulation suggests that the release of mast cell products (histamine, leucotrienes, cytokines, chemokines) leads to alterations in vasopermeability, upregulation of adhesion molecules on endothelial cells, and rolling and attachment of blood leukocytes, followed by chemotaxis and transendothelial cell migration.

2.2 Autoimmunity and chronic urticaria

The first suggestion that patients with chronic urticaria and angioedema might have an autoimmune diathesis was the observation that there is an increased incidence of antithyroid antibodies in such patients relative to the incidence in the population at large. These include antimicrosomal (perioxidase) and antithyroglobulin antibodies, as seen in patients with Hashimoto’s thyroiditis. The incidence of antithyroid antibodies in chronic urticaria, as reported in the literature, varies between 15% and 24%, but the most recent data are closer to the latter figure and demonstrate segregation of antithyroid antibodies with chronic autoimmune urticaria rather than chronic idiopathic urticaria. Another theories was suggested that existing an IgG antibody reactive with the α subunit of the IgE receptor; in addition a 5%–10% incidence of functional anti-IgE antibodies was confrmed.

2.3 Cellular infiltrate

Pathology reveals perivascular infltrate that surrounds small venules within the superfcial and deep venular plexus, with a prominence of CD4+ T lymphocytes and monocytes and virtually no B cells. Granulocytes are quite variable but are plentiful if the lesion undergoes biopsy early in its development. Neutrophils and eosinophils are both present although the degree of eosinophils accumulation varies greatly. Even when eosinophils are not evident, major basic protein can be identifed within lesions (in at least two-thirds of patients), which most likely represents evidence of prior eosinophil degranulation. The presence of basophils has also been recently demonstrated by using an antibody (BB1) that is specific for this cell type. Thus, the infltrate resembles that of an allergic late-phase reaction, as suggested previously, although the percentage of each cell types differs, with neutrophils and monocytes being relatively more prominent in urticaria. Endothelial cell activation is suggested by the presence of intercellular adhesion molecule 1 and E-selectin in biopsy specimens of urticarial lesions. Sources of chemokines include the mast cell and the activated endothelial cell; the latter cells are stimulated not only by cytokines or monokines, such as IL-4, IL-1, and tumor necrosis factor-α (TNF-α), but also by the vasoactive factors, for example, histamine and leukotrienes released from activated mast cells.

2.4 Role of bradykinin in angioedema

Kinins are low-molecular-weight peptides that participate in inflammatory processes by virtue of their ability to activate endothelial cells and, as a consequence, lead to vasodilatation, increased vascular permeability, production of nitric oxide, and mobilization of arachidonic acid. Kinins also stimulate sensory nerve endings to cause a burning dysesthesia. Thus, the classical parameters of inflammation (i.e., redness, heat, swelling, and pain) can all result from kinin formation. Bradykinin is the best characterized of this group of vasoactive substances.

There are two general pathways by which bradykinin is generated. The simpler of the two has only two components: (1) an enzyme tissue kallikrein and (2) a plasma substrate, low-molecular-weight kininogen. Tissue kallikrein is secreted by many cells throughout the body; however, certain tissues produce particularly large quantities. These include glandular tissues (salivary and sweat glands and pancreatic exocrine gland) and the lung, kidney, intestine, and brain. The second pathway for bradykinin formation is far more complex and is part of the initiating mechanism by which the intrinsic coagulation pathway is activated. Factor XII is the initiating protein that binds to certain negatively charged macromolecular surfaces and autoactivates (autodigests) to form factor XIIa. There are two plasma substrates of factor XIIa, namely  prekallikrein and factor XI and each of these circulates as a complex with high-molecular-weight kininogen (HK). These complexes also attach to initiating surfaces, and the major attachment sites are on two of the domains of HK, which thereby places both prekallikrein and factor XI in optimal conformation for cleavage to kallikrein (plasma kallikrein) and factor XIa, respectively. It is important to note that plasma kallikrein and tissue kallikrein are separate gene products and have little amino acid sequence homology, although they have related functions (i.e., cleavage of kininogens). Tissue kallikrein prefers low-molecular-weight kininogen but is capable of cleaving HK, whereas plasma kallikrein cleaves HK exclusively.

  1. CLINICAL FEATURES

Urticaria is characterized by wheals which are circumscribed, raised, usually very pruritic, areas of edema, about 1-8 cm in size, surrounded by red or white, round or oval or polyarchy macules. The wheals usually spread into large patches. Duration of survival is short, usually less than 24 hours.

Angioedema: when the edematous process extends into the deep dermis and/or subcutaneous and submucosal layers, it is known as angioedema. Angioedema commonly affects the face (eyelids, lips, tongue) or a portion of an extremity. When angioedema affects the larynx, it may cause shortness of breath.

Urticaria and angioedema may occur in any location together or individually.

  1. CLASSIFICATION

4.1 Base on the time

4.1.1 Acute urticaria

Acute urticaria is sudden in onset, manifested by large wheals, usually with angioedema, that is present for less than 6 weeks. It is often gone within hours to days. It usually relate to atopic individuals, IgE, foods, parasites and drugs (eg., penicillin)

4.1.2 Chronic urticaria

Chronic urticaria  is urticaria that persists for more than 6 weeks. The wheals are usually small or widespread. Chronic urticaria are rarely associated with IgE but are associated with to FcεRI autoantibodies. In approximately 80% of the cases, the cause was not discovered and are considered idiopathic. The disease mainly affects adults and women more than men.

4.2 Pathogenesis-related specific types

4.2.1 Immunological urticaria

– IgE mediated

The lesions are caused by releasing biological active substances by mast cells or eosinophils that were sensitive to specific antigen. It usually occurs on an atopic individual. Common antigens are food (milk, eggs, flour, seafood, nuts) and drugs (penicillin). Acute onset.

– Complement mediated

Activating the complement by the immune pathway and releasing anaphylatoxin. Ultimately, this processes cause granulation of mast cells.

– Autoimmune

This condition is chronic and common with FcεRI autoantibodies and/or IgE. Clinically, there is no difference between chronic urticaria with or without autoantibodies. It responds to plasma filtration, intravenous immunoglobulin or cyclosporine

– Immunologic contac urticaria

Common in children with atopic dermatitis who was sensitive to environmental allergens (grass, animals). It also occurs in people who were sensitive to rubber gloves containing latex particles.

4.2.2 Physical urticaria

– Dernographism

A lesion appears as a linear wheal with a flare at a site in which the skin is briskly stroked with a firm object. A transient wheal appears rapidly and usually fades within 30 minutes. The prevalence of dermographism in the general population was reported as 4.2%.

– Cold urticaria

Usually occurs in children and young people. The urticaria lesions are limited to the cold exposed areas and go away within minutes. The “ice cube” test (skin exposes to cold ice for a few minutes) helps diagnose this disease.

– Solar urticaria

Urticaria occurs after exposure to sunlight with a wavelength of 290-500 nm. The wheals last less than 1 hour, and may be associated with fainting

– Cholinergic urticaria

Often appears after a lot of exercise, exertion, excessive sweating. Lesions include small, very itchy wheals that may be accompanied by wheezing and tearing.

– Aquagenic urticaria

Rarely, this condition results from contacting with water at any temperature. The lesions are similar to cholinergic urticaria.

– Pressure angioedema

Delayed pressure urticaria appears as erythematous, deep, local swellings, often painful, that may last several days. Spontaneous episodes are elicited on areas of contact after sitting on a hard chair, under shoulder straps and belts, on the feet after running, and on the hands after manual labor. Delayed pressure urticaria may occasionally be associated with fever. Laboratory tests were normal. It may be associated with urticaria lesions

– Vibration angioedema

Rarely, hereditary (dominant autosomal disease). Vibration stimulations cause the release of histamine from mast cells as rubbing a towel on the back causes urticaria lesions while direct compression does not.

4.2.3 Urticaria due to mast cell-releasing agents and pseudoallergens and chronic idiopathic urticaria non-immune contact urticaria

Urticaria/angioedema, and even anaphylaxis-like symptoms can occur when exposed to radiocontrast media, or as a result of salicylate intolerance, preservatives, food additives (such as benzoic acid, benzoate salts) as well as dyes including tartrazine (pseudo-allergen). It may be acute or chronic. In idiopathic chronic urticaria, histamine from mast cells in the skin is the main chemical mediator.

– Non-immune contact urticaria

As foreign irritants (such as sorbic acid, benzoic acid in foods and eye drops, acetylcholine, serotonin) enter the skin or blood vessels, the lesions are localized at the site of contact.

4.2.4 Urticaria associated with vascular/connective tissue autoimmune disease

Urticarial lesions may be associated with systemic lupus erythematosus (SLE) and Sjögren syndrome. However, in most instances, they represent urticarial vasculitis. Urticarial lesions persist for more than 12 hours to 24 hours, are slow to change in size and morphology, may be associated with purpura, leaving a hyperpigmented macule due to hemosiderin deposition. It often associated with a decrease in complement in the blood and kidney disease.

4.2.5 Angioedema syndromes with or without urticaria

– Hereditary angioedema

This is a dangerous, hereditary disorder (dominant autosomal disease). Manifestations of the disease are edema of face, limb, larynx, acute abdominal pain due to edema of the intestinal wall that resembles a surgical emergency. It is rarely accompanied with urticaria lesions. Abnormal tests involving the complementary system: reduced C1-esterase inhibitors, decreased C4 while normal C1 and C3 levels. Angioedema may be due to the formation of bradykinin because the C1-esterase inhibitor is the main inhibitor of Hageman and kallikrein factors, two enzymes needed for the formation of bradykinin, so when C1-esterase is inhibited, bradykinin is excessively produced.

– Angioedema-urticaria-eosinophilia syndrome

This condition manifests by severe angioedema, occasionally itchy urticarial wheals, involving the face, neck, limb, trunk, lasting 7-10 days. The rest was normal. The CBC test showed an elevated white blood cell count (20,000-70,000/µL) of which eosinophils accounted for 60-80% and were associated with the severity of the disease. The disease is rare, non-hereditary with good prognosis.

  1. LABORATORY FINDINGS

5.1 Histopathology

Edema involving the superfcial portion of the dermis is characteristic of urticaria, whereas angioedema involves the deeper dermis and subcutaneous tissue. Both disorders are associated with dilatation of the venules and without vascular damages. Perivascular infiltration of inflammatory cells, particularly active lympho cells.

5.2 Serology

– Detect antigens related to Hepatitis B virus.

– Quantification of IgE, FcεRI autoantibodies.

– Immunoassay tests for SLE and Sjögren syndrome.

5.3 Blood test

– Elevate ESR (Erythrocyte Sedimentation Rate)

– Decresed complement levels

– Transient elevated eosinophils in patients who are allergicto foods, parasites and drugs. High eosinophilia in angioedema-urticaria-eosinophilia syndrome.

5.4 Complement

Screening for C1 inhibitors in hereditary angioedema

5.5 Ultrasound

Publish early diagnosis of abdominal pain related to hereditary angioedema.

5.6 Test for parasite and bacteria

– Stool test for detecting intestinal parasites

– Gastroscopy for Helicobacter pylori in patients with peptic ulcer disease.




  1. APPROACH TO URTICARIA AND ANGIOEDEMA
Figure 5. Approach to patient with urticaria/angioedema

 

 

  1. PROGNOSIS

About half of urticaria patients resolve symptoms within 1 year, but 20% of cases last more than 20 years. The prognosis is good excluding hereditary angioedema (this condition can lead to death if untreated)

  1. TREATMENT

8.1 Prevention

– Avoid identified allergens such as food, some medicines.

– Avoid the irritation causing physical urticaria.

– Treatment of parasitic and bacterial infections.

8.2 Medicines

– H1 Antihistamines: such as hydroxyzine, terfenadine, loratadine, cetirizine and fexofenadine. Fexofenadine 180 mg/day or loratadine 10-20mg/day provide well control the symptoms of urticaria, however symptoms recur when the medication is discontinued. H1 Antihistamines  may be combined with H2 antihistamines (such as cimetidine) and/or mast cell stabilizers (ketotifen). According to the recommendations of European dermatologists, second generation H1 antihistamines can be used at a dose 2-4 times higher than the usual dose in cases of chronic urticaria that respond poorly to usal dose – therapy after two weeks.

– Corticosteroid: Used in cases of acute urticaria with angioedema and angioedema-urticaria-eosinophilia syndrome

– Danazol or stanozolol: Prolonged therapy for hereditary angioedema.

– Other measures: In chronic idiopathic or autoimmune urticaria, if the disease does not respond to antihistamines, cyclosporine and anti-IgE (Omalizumad) may be used. In addition, other methods such as plasma filtration and intravenous immunoglobulin may be used.

References
1.     Bernstein JA (2005), “Chronic urticaria: an evolving story”, Isr Med Assoc J  7(12): 774-7.
2.      Boezova E, Grattan CE (2008), “Urticaria, angioedema, and anaphylaxis”, Clinical immunology principles and practice, 3rd ed, Philadelphia, pp. 641-656.
3.     Gaig P et al (2004), “Epidemiology of urticaria in Spain”, J Invest Allergol Immunol 14: 214.4.     Kaplan  AP (2008), “Urticaria and angioedema”, Fitzpatrick’s Dermatology in General Medicine, 7th ed, New York, McGraw-Hill, 2008, p. 339.
5.     Hide M et al (1993), “Autoantibodies against the high-affinity IgE receptor as a cause of histamine release in chronic urticaria”, N Engl J Med 328:1599.
6.     Leznoff A et al (1983), “Association of chronic urticaria and angioedema with thyorid autoim”, Arch Dermatol 119:636.
7.     Smith JM (1991), “Epidemiology and natural history of asthma, allergic rhinitis and atopic dermatitis”, Allergy and immunology clinical science 26(2): 891-924.
8.     Zweim B et al (2000), “Sequential patterns of inflammatory events during developing and expressed skin late-phase reactions”, J Allergy Clin Immunol 105: 776.

Author: Dr.Trần Thị Huyền
Publisher: Social Work Department