Urticaria

 

Salient features

 

·        Urticaria is defined as a skin disorder characterized by local transient skin or mucosal edema (wheal) and an area of redness (erythema) that typically accompanies itchy sensations and diminishes within 1 day.

·        Symptoms may occur either spontaneously (spontaneous or idiopathic urticaria) or in response to specific stimuli, such as physical stimuli or sweating (the increase of body core temperature).

·        Mast cells and their histamine being released either spontaneously or in response to various stimuli play a crucial role in the pathogenicity of urticaria.

·        Spontaneous or idiopathic urticaria is the subtype of urticaria that most patients experience.

·        Autoantibodies against immunoglobulin (Ig) E or the high-affinity IgE receptor (FcεRI) that activate mast cells and basophils and induce histamine release may be detected in up to half of patients with chronic spontaneous or idiopathic urticaria (type II autoimmunity).

·        There are several recognizable clinical patterns of urticaria and different causes. The latter include allergy, autoimmunity, drugs, dietary pseudo allergens, and infections. Many cases of spontaneous urticaria remain unexplained (“idiopathic”) even after an extensive evaluation.

·        A certain population of patients may develop angioedema mediated by bradykinin rather than histamine.

·        Diagnosis is based primarily on the history and clinical examination. Determination of the etiology or triggers, as well as exclusion of other diagnoses, may require further investigations, including blood tests, physical and dietary challenges, skin tests, and skin biopsy

·        Nonsedative second-generation antihistamines are the mainstay of pharmaceutical therapy.

·        Omalizumab, anti-IgE antibody, or immunosuppressive medications may be taken for the treatment of urticaria and angioedema that is refractory to antihistamines even at high doses.

 

Introduction

The urticarias are characterized by short-lived swellings of the skin and mucosa due to plasma leakage. The term ‘urticaria’ is a disease that may present with weals, angioedema or both. Weals and angioedema often occur together and are similar processes resulting from superficial and deep swellings, respectively.

The triple response of Lewis is a cutaneous response that occurs from firm stroking of the skin, which produces an initial red line, followed by a flare around that line, and then finally a wheal. The triple response of Lewis is due to the release of histamine and consisting of:

1.   Red spot: due to capillary dilatation

2.   Flare: redness in the surrounding area due to arteriolar dilatation mediated by axon reflex.

3.   Wheal: due to exudation of fluid from capillaries and venules due to increased vasopermeability.

 

 

 

Wheals are swellings of the superficial dermis due to edema of the papillary body and are itchy, well-demarcated, non-pitting, raised swellings of the skin, pink or pale in the center, often with a surrounding red flare initially. They occur anywhere on the body, any numbers, sizes, and shapes and individual lesions resolve spontaneously within 24 h, leaving the skin with a normal appearance.

 

Angioedema swellings occur deeper in the dermis and in the subcutaneous or submucosal tissue. Angioedema usually affects the most distensible tissues, such as the eyelids, lips, ears lobes and external genitalia, or the mucous membranes of the mouth, tongue, pharynx or larynx or a portion of an extremity such as hands or feet. The areas of involvement tend to be normal or faint pink in color, painful rather than itchy (fewer type C nerve endings in the deeper cutaneous levels), larger and less well defined than wheals, and usually lasting for up to 3 days. Depending on the location (tongue, throat, glottis), there may be an acute risk of suffocation.

 

Thus wheal and angioedema are thus the same edematous process but involving different levels of the cutaneous vascular plexus: papillary and deep.

 

Anaphylaxis is an acute, severe, life-threatening, systemic reaction often involving the skin due to mast cell mediator release that may be allergic or non‐allergic. It consists of a combination of symptoms and signs, including diffuse erythema, pruritus, urticaria and angioedema, hypotension and difficulty in breathing.

 

Epidemiology

 

Incidence and prevalence

 

An estimate of the lifetime occurrence of urticaria is likely to be in the range of 1–5% in the general population.

Age

 

Urticaria may occur at any age. Acute spontaneous urticaria often presents in childhood but the peak incidence of chronic spontaneous urticaria is in the fourth to fifth decades.

 

Sex

 

Women outnumber men by 2: 1 with chronic spontaneous urticaria but there is no sex difference in either acute spontaneous urticaria or the inducible urticarias.

Pathophysiology

Mast cells and basophils

Mast cells settle in connective tissues and usually do not circulate in the blood stream.

Basophils are the smallest circulating granulocytes. They arise in the bone marrow, and following maturation and differentiation, are released into the blood circulation. If they are adequately stimulated they may settle in the tissues.

Both mast cells and basophils contain special cytoplasmic granules which store preformed mediators of inflammation. The extracellular release of the mediators is known as degranulation.

Two types of mast cells have been found by immunohistochemical analyses. The MC_TC type contains neutral proteases tryptase and chymase and predominates in normal skin and intestinal submucosa, whereas the MC_T type contains only tryptase, and predominates in normal intestinal mucosa and lung alveolar wall. Nearly equivalent concentrations of each type are found in nasal mucosa. Both types, however, express high-affinity IgE receptors (FcϵRI) and are therefore capable of participating in IgE-dependent allergic reactions.

Mast cell activation

The mast cell is the primary effector cell of urticaria. Mast cells are widely distributed throughout the body but vary in their phenotype and response to stimulation. This may explain why systemic features, such as those seen in anaphylaxis, do not accompany the activation of cutaneous mast cells in urticaria.

Mast cell may be activated by immunological stimulation with activation of the high-affinity IgE receptor (FcεRI) or by non-immunological IgE-independent stimulation (e.g., by direct histamine liberation of opiates or neurotransmitters such as substance P, physicochemical stimuli, by pseudo allergens such as acetylsalicylic acid, infections via possible complement activation, immune complexes, pathogen-specific IgG or IgE, bacterial toxins).

Immunological (Allergic)

Cross-linking of two or more adjacent α-subunits of high-affinity IgE receptors (FcεRIα) on the mast cell membrane will initiate a chain of calcium- and energy-dependent steps leading to fusion of storage granules with the cell membrane and externalization of their contents. This is known as degranulation. Classic immediate hypersensitivity reactions involve binding of receptor-bound specific IgE by allergen. There are also several recognized immunologic degranulating stimuli that act through the IgE receptor, such as anti-IgE and anti-FcεRI auto antibodies. However, not all auto antibodies with these specificities are functional, i.e. capable of releasing histamine from mast cells or basophils in vitro.

Non-immunological (Non- allergic)

Drugs, including opiates such as morphine and codeine, vancomycin and polymyxin; some radiocontrast media; and some foods, such as strawberries; C5a anaphylatoxin, stem cell factor and neuropeptides (e.g. substance P), can cause mast cell degranulation by binding specific receptors, independent of the FcϵRI.

Immunological and non‐immunological mast cell degranulation stimuli. The mast cell responds with degranulation to non‐immunological as well as immunological stimuli in vitro. It is often difficult, if not impossible, to know the exact cause of degranulation in vivo. PAMPs, pathogen‐associated molecular patterns; SCF, stem cell factor; SP, substance P.

 

Proinflammatory mediators

There are two categories of pro inflammatory mediators in mast cells and basophils. 

Preformed mediators, stored in secretory granules and secreted upon cell activation, include a biogenic amine, typically histamine, proteoglycans, either heparin, chondroitin sulphates or both, and a spectrum of neutral proteases.

Newly generated mediators, often absent in the resting mast cells, are typically produced during IgE-mediated activation and consist of arachidonic acid metabolites, principally leukotrienes and prostaglandin and platelet activating factor. Prostaglandins and leukotrienes are synthesized from arachidonic acid derived from cell membrane phospholipids. The most important pro inflammatory eicosanoids are prostaglandin (PG) D₂ and the leukotrienes (LT) C₄, D₄ and E₄ (slow releasing substance of anaphylaxis). PGE₂ has inhibitory effects on immunologic mast cell degranulation and may therefore have a protective role in urticaria.

Mast cells can produce a wide variety of cytokines. Newly synthesized cytokines are IL-2, IL-3, TNFα, IL-4, IL-5, IL-6, IL-8, and IL-13. Some cytokines are pre-made and stored in granules for immediate release upon activation (IL-4, TNFα, and GM-CSF).

Both preformed and newly synthesized pro inflammatory mediators are released from mast cells upon activation.

 

Blood Vessels

Histamine and other proinflammatory mediators released on degranulation bind receptors on post capillary venules in the skin, leading to vasodilation and increased permeability to large plasma proteins, including albumin and immunoglobulins. Furthermore, histamine, TNF-α, and IL-8 up-regulate the expression of adhesion molecules on endothelial cells, thereby promoting the migration of circulating inflammatory cells from the blood into the urticarial lesion.

 

Blood

 

Autoantibodies

 

Functional IgG auto antibodies against IgE or the high‐affinity IgE receptor that release histamine (and other mediators) from mast cells and basophils have been detected in the serum of 25–30% of patients with chronic spontaneous urticaria. Binding of the auto antibodies to mast cells and basophils may initiate complement activation with the generation of C5a anaphylatoxin, which in turn facilitates or augments degranulation.

 

Leukocytes

 

Blood basophils are reduced in number in chronic ordinary urticaria patients. Basophils are recruited into urticarial wheals after weal initiation and may contribute to the persistence of wheals by releasing histamine and other mediators.

Eosinophil, neutrophil and lymphocyte numbers are normal in the peripheral blood, but these cells are often present in wheals. Eosinophils may contribute to the persistence of wheals by generating LTC₄, LTD₄ and LTE₄ and by releasing toxic granule proteins, including major basic protein (MBP), which can release histamine from basophils. The function of neutrophils and lymphocytes in urticaria has not been elucidated.

Neuropeptides

Some mast cells are positioned close to nerve endings. Histamine can stimulate sensory afferent nerves to release substance P, responsible for the neurogenic axon flare.

 

Mechanisms of Urticaria Formation

Mast cell-dependent urticaria

Cross-linking of the Fab portion of specific IgE on mast cells by percutaneous or circulating allergen undoubtedly accounts for some cases of acute or episodic urticaria, but this is probably never the cause of chronic spontaneous urticaria. Examples of the former would be contact urticaria from natural rubber latex and acute urticaria from foods, including nuts, fish, and fruit. However, the majority of acute urticaria cases do not relate to allergen exposure. Binding of pathogen‐associated molecular patterns (PAMPs) on microbes to toll‐like receptors on mast cells may be relevant to the pathogenesis of acute urticaria, which is more often linked to acute viral or bacterial infections than any other etiology but experimental proof for this is lacking.

 

It is often difficult to know the exact pathogenesis of individual cases of urticaria, and many cases remain idiopathic after evaluation.

IgE has been implicated in the pathogenesis of symptomatic dermo­graphism, cold urticaria and solar urticaria, but the mechanism by which it renders skin mast cells more sensitive to physical stimulation is not certain. It is proposed that the physical stimulus in these patients induces a neoantigen that reacts with specific IgE antibody bound to mast cells. An additional mechanism, such as neuropeptide release, could initiate or potentiate mast cell activation. Using electron microscopy, localized platelet clumping has been demonstrated in cold urticaria, and the release of platelet mediators, including platelet-activating factor (PAF) and platelet factor 4/CXCL4, could contribute to wheal formation.

 

Cholinergic urticaria develops in response to stimulation of cholinergic sympathetic innervation of the sweat glands. How release of acetylcholine from the nerve endings leads to mast cell activation and histamine release is unknown. An allergy to sweat has been demonstrated by one group of investigators. It has been proposed that pressure-induced wheals may be due to a late-phase reaction, but an antigen has never been identified.

 

The initiating event for spontaneous urticaria wheals is unclear but may involve plasma leakage due to local factors such as heat or pressure, which allows the extravasation of auto antibodies or IgE-directed antigens that then activate the IgE receptor, thus leading to mast cell degranulation and a subsequent urticarial response. As functional auto antibodies cannot be detected in ~70% of chronic urticaria sera by currently available tests, other mechanisms may operate in “non-autoantibody” urticaria, which, nevertheless, has a similar clinical presentation. Increased plasma levels of prothrombin fragment 1 + 2 (F 1 + 2) and D-dimer (a measure of fibrinolysis) have been demonstrated in CSU and relate to disease severity, but the contribution of coagulation abnormalities to the pathogenesis remains unclear.

 

A popular hypothesis is that dietary food additives and natural salicylates as well as nonsteroidal anti-inflammatory drugs (NSAIDs) may cause urticaria via the diversion of arachidonic acid metabolism from prostaglandin to leukotriene formation. The whealing is caused by direct action of LTC₄, LTD₄, and LTE₄ on small blood vessels. There is some evidence that PGE₂ can have inhibitory effects on immunologic mast cell degranulation, so a reduction in their formation may facilitate the latter. Aspirin can aggravate urticaria in up to 30% of patients with chronic disease, and so avoidance of dietary pseudo allergen give encouraging results. Aspirin allergy as a cause of urticaria is much less common, and the proportion of patients with urticaria due solely to pseudo allergens is probably low.

Understanding “idiopathic” urticaria remains an important challenge. From a clinical perspective, it should be regarded as a multifactorial problem, and searching for aggravating factors is just as important as looking for causes.

 

Mast cell-independent urticaria

 

There are several recognized circumstances where angioedema or wheals are due to mechanisms that do not involve mast cells. These need special consideration because their management and prognosis are different. For example, prostaglandins are involved in the pathogenesis of some patterns of non-immunologic contact urticaria (e.g. to benzoic acid), and the latter can be suppressed by NSAIDs. In the cryopyrin-associated periodic syndromes (CAPS), patients often develop urticarial lesions. Systemic symptoms, such as fever, help to distinguish patients with autoinflammatory syndromes from those with CSU. The significant improvement that results from the administration of anakinra, an IL-1 receptor antagonist, rilonacept, a fusion protein that contains the extracellular domain of the IL-1 receptor and functions as an IL-1 trap, or canakinumab, a human anti-IL-1β monoclonal antibody, points to the role of the cryopyrin inflammasome and its production of IL-1β.

 

Mechanisms of urticaria formation

 

The pathomechanism of weals and angioedema result from transient vasopermeability (due to a local increase in permeability of capillaries and venules and plasma leakage leading to wheals/edema) and vasodilatation of the dermal and subcutaneous vasculature (erythema), axon reflex (erythema halo) as well as stimulation of sensory nerves (itching) following the release of preformed and newly synthesized mast cell mediators. In longer lasting lesions accumulation of immune cells (infiltrate) also occurs. Histamine is the major preformed mediator in most patients. The clinical improvement on treatment with H1 antihistamines underlines the role of mast cell-derived histamine as a major mediator in urticarias. Activation of H1 receptors in the skin induces itching, flare, erythema and wealing whereas activation of H2 receptors contributes to erythema and wealing, but not itch or flare.

The key to diagnosis and therapy is the understanding of the trigger of mast cell activation with degranulation and release of mediators.

 

Possible causes of urticaria

Category	Example
Allergic (IgE-mediated)	Food Medication (β-lactam antibiotics) Aeroallergens Contact allergens Other proteins
Pseudo allergic (not IgE-mediated)	Acetylsalicylic acid (aspirin) Other nonsteroidal anti-inflammatory drugs (NSAIDs) Food additives (additives) Radio contrast media
Physical	Shear forces Vertical pressure Cold Heat Ultraviolet light, visible light
Infections	Bacterial infection (Helicobacter pylori, Streptococcus) Viral infection (flu-like infection) Parasites (e.g., blastocystis hominis)
Autoreactive/autoimmune	Hashimoto’s thyroiditis, Graves’ disease
Paraneoplastic	Lymphoproliferative disease, acute myeloid leukemia, solid tumors
Psychic	Stress Traumatic stress Depression
Increased body temperature	Physical exertion Emotional stress Hot bath or hot shower
Idiopathic

 

Estimated frequency of different etiologies of selected urticaria forms in each of 100 affected adults^a

	Infections	Allergic	Pseudoallergic, not IgE-mediated	Autoreactive	Unknown
Acute spontaneous urticaria	50	10	25	0	20
Chronic spontaneous urticaria	50	<1	20	35	20
Cold urticaria	10	0	0	0	90b
Contact urticaria	0	60	40	0	0
Exercise-induced urticaria	0	30	0	0	70b

^aCombinations are possible

^bTrigger is known, but not the etiology

Mast cells are found in the vicinity of blood vessels, skin adnexae, and nerves. They can be degranulated by immunological stimulation with activation of the high-affinity IgE receptor (FcεRI) or by non-immunological IgE-independent stimulation (e.g., by direct histamine liberation of opiates or neurotransmitters such as substance P, physicochemical stimuli, by pseudo allergens such as acetylsalicylic acid, infections via possible complement activation, immune complexes, pathogen-specific IgG or IgE, bacterial toxins). The activation of FcεRI can be achieved by cross-linking the specific IgE antibodies bound to the receptor (allergic hypersensitivity reaction of immediate type, type I according to Gell and Coombs) or by autoantibodies that bind directly to the receptor or to IgE itself (autoreactive).

The latter has so far only been shown for chronic spontaneous urticaria. In about one-third of patients with chronic urticaria, IgG auto antibodies against IgE or the high-affinity IgE receptor (anti-FcεRI) can be detected, some of which have functional activity on basophilic granulocytes and/or mast cells (induction of histamine release, sulfide-leukotriene production, surface expression of activation markers such as CD63, CD203c). In recent years IgE auto antibodies against thyroid peroxidase, interleukin-24, and staphylococcal exotoxins were detected in some patients with chronic spontaneous urticaria. In addition, the intradermal testing of autologous serum is positive in a subgroup (autologous serum test), but this does not correlate with the presence of the auto antibodies mentioned above.

After activation, the cutaneous mast cells secrete preformed (histamine, heparin, proteases) as well as newly formed (prostaglandins, leukotrienes) mediators and cytokines (tumor necrosis factor α, interleukin-8).

Since antihistamines often do not treat the symptoms adequately, other mast cell mediators (prostaglandins, leukotrienes C4 and D4, bradykinin, and mast cell proteases) are apparently involved in addition to histamine. A role of further immune cells and their mediators, for example eosinophils, basophils or lymphocytes in urticaria, is also suspected.

Recent studies on pathogenesis are focusing on the extrinsic coagulation system (formation of thrombin and fibrin) and the enzyme matrix metalloprotease 9.

At least for chronic spontaneous urticaria, a multifactorial model was developed in which the threshold for the development of urticaria by increased mast cell activation is lower than in healthy individuals. The lowering of the threshold until the development of urticaria could be caused by intrinsic factors (genetic factors such as HLA association, auto antibodies against FcεRI, or unknown factors). External factors such as pseudo allergens or infections could increase the sensitivity of patients and thus explain the variability of the clinical picture in individual patients.

 

Histology of urticaria

The histology of urticarial weals is usually non-specific and shows an edema in the papillary and reticular dermis, dilatation of the small venules of the upper dermis as well as a perivascular infiltrate with predominantly CD4-positive T lymphocytes, monocytes and partially granulocytes (neutrophils, eosinophils, basophils with individually different expressions) in a longer persisting hive. The infiltrate is similar to a late-stage reaction. There is no epidermal involvement. Dermal mast cells in weals of chronic urticaria are increased by 10 times compared with non‐urticated skin. Whether mast cell mediators such as histamine or tryptase are elevated is also not clear. The cellular infiltrate and cytokine pattern in patients with and without functional auto antibodies against IgE or FcεRI are identical.

It is not possible to assess the severity, etiology, or prognosis of urticaria in terms of course or response to therapy by histopathology. Biopsies are therefore only useful to rule out differential diagnoses such as urticaria vasculitis (typical: leukocytoclasia, erythrocyte extravasates, deposits of fibrin, C3, IgG).

 

Clinical features of urticaria

The condition can present at any age. Acute urticaria is common in young children with atopic dermatitis, but chronic urticaria peaks in the fourth decade.

Itching erythematous macules develop into weals and resolve within 2- 24 h, passing through a macular erythematous phase, leaving the skin with a normal appearance. The primary lesion is the wheal, a palpably raised, sharply defined erythema and shows the yellowish color of the serum exudate under pressure with a glass spatula. The axon reflex (signals from skin receptors are also transmitted via collateral to blood vessels) causes an erythema of varying width, around the individual wheals: reflex erythema.

The size, number, and shape of each weal can vary greatly. The typical weals develop within seconds to minutes and usually disappear within 3–4 h. However, new weals may appear at a different location. Usually hives are light red (Urtica rubra), but can also look whitish anemic as a result of compression of superficial vessels by cutaneous edema (Urtica porcellanea). They may occur anywhere on the body, including the scalp, palms and soles and variable in numbers and sizes, ranging from a few millimeters to lesions covering large areas, and of varying shapes including rounded, annular, flowerlike, serpiginous and bizarre patterns due to confluence of adjacent lesions and they are usually heterogeneous. The heterogeneity of weals in size and shape is one of the characteristics of spontaneous urticaria. Very rarely, central blisters may form when edema is intense.

Itching (pruritus) is often described as stinging or burning. They may occur at any time, but often appears in the evening or is present on waking. Irritation tends to be most intense at night (parasympathetic reaction) and may disturb or prevent sleep. This, in turn, compounds the distress of the condition. Patients tend to rub rather than scratch, so excoriation marks are unusual, but occasionally bruising may result, which may be seen particularly on thighs. Palmoplantar tingling paresthesia, nausea, and dizziness indicate an incipient anaphylactic reaction that may turn into anaphylactic shock. Women may describe premenstrual exacerbations.

If the edema occurs in the subcutis, a circumscribed, skin-colored swelling develops, angioedema, which are usually painful rather than itching and can persist for up to 3 days when severe. Although angioedema can also occur anywhere in the body, it is more common on the lids, lips, and genitals, sometimes affecting the tongue, glottis, or larynx (early sign: hoarseness) and can become life-threatening. The localization changes and is usually asymmetrical.

Around 50% of patients with spontaneous urticaria describe angioedema associated with wealing at some time of the illness and about 10% describe angioedema without weals.

Systemic symptoms of fatigue, lassitude, sweats and chills, indigestion, myalgia or arthralgia may occur with severe attacks, but the occurrence of pyrexia or arthritis should alert the clinician to another explanation, such as urticarial vasculitis.

 

Classification

Urticaria is broadly classified by duration of disease and clinical features. When urticaria is present daily or almost daily for less than 6 weeks it is called acute. If urticaria occurs continuously on most days lasting for 6 weeks or more, it is called chronic. The acute and chronic terminology is usually applied to spontaneous urticaria but inducible urticarias may also be acute or chronic, depending on their duration.

 

URTICARIA – CLINICAL CLASSIFICATION AND DIFFERENTIAL DIAGNOSIS
Clinical classification
·       Spontaneous urticaria (all urticarias not classified below) 1.   Acute 2.   Intermittent (episodic) 3.   Chronic (previously known as ‘idiopathic’)   ·       Inducible urticarias   1.   Physical and cholinergic urticarias   2.   Contact urticaria (induced by percutaneous or mucosal penetration)*
Differential diagnosis
·       Urticarial vasculitis (defined histologically by leukocytoclastic vasculitis)   ·       Angioedema without wheals (e.g. hereditary angioedema, ACEi-induced angioedema)   ·       Distinctive urticarial syndromes (e.g. autoinflammatory syndromes) presenting with urticarial rash

ACEi= angiotensin-converting enzyme (ACE) inhibitor.

 

Classification of the most common forms of urticaria

Spontaneous urticaria		Inducible urticaria (physical forms)		Inducible urticaria (special forms)
Subtype	Definition	Subtype	Definition	Subtype	Definition
Acute spontaneous urticaria	<6-week period of spontaneous hives	Symptomatic dermographism (urticaria factitia)	Occurs as a result of mechanical shear forces (latency 1–10 min)	Contact urticaria	Occurs as a result of contact with urticariogenic substance
Chronic spontaneous urticaria	>6-week period of spontaneous hives	Cold urticaria	Occurs as a result of contact with cold (air/water/wind/objects)	Cholinergic urticaria	Arises from increased body temperature
		Heat urticaria	Occurs as a result of contact with local heat (air/water/wind/objects)	Exercise-induced urticaria	Arises from physical exertion
		Delayed pressure urticaria	Arises from vertical pressure (latency 3–8 h)	Aquagenic Urticaria	Occurs as a result of contact with water (temperature-independent)
		Solar Urticaria	Arises from UV and/or visible light
		Vibratory urticaria/angioedema	Occurs through vibration

The most common is the clinical classification, which defines spontaneous urticaria and inducible urticaria (physical urticaria and special forms). In contrast to spontaneous urticaria, physical urticaria and special forms are also known as inducible urticaria.

About 80% of urticaria is spontaneous, 10% is physical, and less than 10% belong to a special form.

Two or rarely more urticaria types may occur in the same patient (e.g., chronic spontaneous urticaria and symptomatic dermographism or chronic spontaneous urticaria and delayed pressure urticaria).

In patients with two or more types of urticaria, urticaria is usually protracted and difficult to treat.

 

Spontaneous urticaria

Acute versus Chronic Urticaria

All urticarias are acute initially. Some will become chronic after a period 6 weeks or more. The term “chronic urticaria” should only be applied to continuous urticaria occurring at least twice a week off treatment. Urticaria occurring less frequently than this over a long period is better called episodic (or recurrent), because this presentation is more likely to have an identifiable environmental trigger.

 

Acute Spontaneous Urticaria

Definition

Acute spontaneous urticaria is defined as spontaneous occurrence of hives, possibly accompanied by angioedema, over a period of less than 6 weeks, 99% of cases persist only for a maximum of 3 weeks.

Epidemiology

Acute urticaria is the most common type of urticaria and accounts for about one-third of all forms of urticaria and two-thirds of spontaneous urticaria. Lifetime prevalence is between 15% and 20%. Younger age is more common, especially in children with atopic dermatitis. Both sexes are affected approximately equally frequently. Due to the acute appearance, acute urticaria is often seen in emergency rooms.

Etiopathogenesis

Most common is acute spontaneous non-allergic urticaria, mostly in association with an acute infection of the upper respiratory tract (30–62%), the urinary tract, and the gastrointestinal tract, often in combination with a non-allergic (pseudo allergic) reaction, e.g., the simultaneous use of nonsteroidal anti-inflammatory drugs (especially cyclooxygenase I inhibitors such as acetylsalicylic acid). The inhibition of the cyclooxygenase pathway by nonsteroidal anti-inflammatory drugs leads to an increased accumulation of leukotrienes instead of prostaglandins in the arachidonic acid metabolism, so that the inhibitory influence of prostaglandin E2 on mast cell granulation and leukotriene production is attenuated.

Acute spontaneous allergic urticaria may also be caused by an IgE-mediated allergy (e.g., to food allergens). Although most patients with acute spontaneous urticaria suspect an allergy to a food, this is rarely the trigger and is more common in atopic patients, especially small children with extrinsic atopic dermatitis (such as cow’s milk, hen’s eggs, wheat, soy and peanut). Acute spontaneous allergic urticaria can also occur in both atopic and non-atopic patients through medication (β-lactam antibiotics) or hymenoptera stings (bee venom, wasp venom). Many patients has an IgE-mediated type I allergy against a fish nematode Anisakis simplex been reported as the trigger of acute urticaria (anisakiasis) after eating raw or insufficiently cooked fish.

Clinical Features

The hives are mostly light red and larger than 1 cm in diameter. In about 40% of patients, more than half of the body surface is affected and systemic accompanying symptoms such as shortness of breath (7%), exhaustion, nausea, or diarrhea occur.

Diagnostic Procedure

A specific diagnostic marker does not exist. The diagnosis of acute urticaria is based on a careful history of potential trigger factors (atopic diseases, known allergies, medication, food intake, insect bites, and signs of infection) and a physical examination.

If no cause can be determined by history, further examinations are not indicated in acute spontaneous urticaria due to the self-limiting course of the disease.

Only the determination of a differential blood count with erythrocyte sedimentation rate or C-reactive protein is recommended as non-specific indicators of inflammation or infection. The detection of a specific IgE-mediated sensitization (prick test, specific IgE antibodies) should be performed if there are indications for an allergic reaction.

Course

In more than 90% of cases acute spontaneous urticaria shows a self-limiting course within 2–3 weeks without recurrence. Although any chronic spontaneous urticaria must by definition have started as acute urticaria, it is not possible to predict which patients will develop chronic spontaneous urticaria. Adequate symptomatic therapy of acute spontaneous urticaria may prevent progression to the chronic form.

Therapy

Trigger factors, such as allergens or drugs, should be identified and avoided and infections adequately treated. Inpatient admission is indicated in cases of shortness of breath, circulatory disorders, and generalized, severe urticaria as well as threatening angioedema. The primary symptomatic therapy for acute spontaneous urticaria consists of H1 antihistamines (in alphabetical order): bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, and loratadine. In the absence of a response to the standard dose after 2 weeks an up to fourfold dose increase should be considered (off-label use, potential side effects of the dose increase should be considered). The second choice is the additional, short-term administration of oral glucocorticoids (40–50 mg prednisolone equivalent per day for 3–4 days).

In severe acute cases (associated severe angioedema), initial intravenous administration of glucocorticoids (up to 100–250 mg prednisolone equivalent) in parallel with an antihistamine may be required, even repeatedly. In the case of progression to anaphylactic shock, the patient must be treated with epinephrine as soon as possible.

The administration of calcium has no rational basis.

 

Acute Spontaneous Urticaria in Childhood

 

Urticaria in childhood is usually acute spontaneous urticaria. Angioedema is present in more than half of cases. The diagnostic procedures as well as the therapy of acute spontaneous urticaria in childhood do not differ fundamentally from the procedures in adults. In children, especially infants with atopy, particular attention should be paid to potential IgE-mediated triggers (especially food allergens such as cow’s milk, hen’s eggs, soy, wheat, and fish). Cow’s-milk allergy is the commonest cause of urticaria in infants under 6 months old. In infants, there may be less itching and a greater tendency for weals to become purpuric. A common pattern is one of bizarrely shaped weals, not seen as frequently in adults.

Newer H1 antihistamines, which are also available as syrup, should be preferred to older preparations with more side effects in children.

 

Causes of acute urticaria

 

Potential allergic causes of acute urticaria

·        Idiopathic

·        Infections

1. Viral, e.g. upper respiratory tract infections, hepatitis B and C
2. Bacterial, e.g. Streptococcus pyogenes
3. Parasitic, e.g. Anisakis simplex

·        Foods, e.g. cow's milk, hen's egg, nuts, seeds

·        Drugs, e.g. β‐lactam antibiotics

·        Stings, e.g. bee, wasp venoms

·        Blood products, e.g. transfusions

·        Vaccines

·        Contactants, e.g. latex

 

Acute spontaneous urticaria

Allergic

 

Any drug, food, foreign substance from blood transfusion, injection, implant, contactant and inhalant should be considered as a potential allergen. Acute urticarial reactions from drugs are common, usually occurring within hours of drug administration in presensitized patients.

Acute urticarial reactions to food are believed to be common and many go unreported. Urticarial reactions may not be to the main food itself but to other ingredients, such as seeds or spices. Rarely, allergic reactions to food occur only if intake is followed by exercise, with neither food nor exercise alone inducing weals (food‐dependent exercise‐induced anaphylaxis). Substances reported to cause this include wheat, hazelnuts and shellfish.

 

Non‐allergic

 

Histamine liberators

 

Mast cell histamine release is non‐immunological and may occur after first exposure. Examples include morphine, codeine, neuromuscular blocking agents, such as atracurium, and antibiotics, such as polymyxin and vancomycin. Iodinated radiocontrast dyes may cause non‐allergic anaphylaxis.

 

Pseudo allergic reactions

Common drug causes include aspirin and other non‐steroidal anti‐inflammatory agents. By inhibiting the cyclo‐oxygenase (COX‐1) pathway of arachidonic acid metabolism, pro‐inflammatory lipoxygenase pathway products leukotriene C₄, D₄ and E₄ are generated with inhibition of prostaglandin E₂, which is inhibitory for immunological mast cell degranulation.

Alcoholic beverages can aggravate urticaria non‐specifically. White wines are often treated with sulphites, which have rarely been reported to cause urticaria and anaphylaxis. Some red wines contain measurable concentrations of vasoactive amines including histamine, which could aggravate urticaria.

Food may also contain vasoactive amines including histamine (such as in cheese, fish, processed meat, tomatoes, pineapple and avocados) or histamine‐releasing substances (such as in strawberries). Histamine generated in scombroid fish (under processed tuna) by histidine decarboxylase from bacteria can cause acute flushing, urticaria, vomiting and diarrhea. High levels of histamine can usually be found in affected fish.

 

Infections

 

Urticaria may follow non‐specific viral infections, or acute hepatitis B viral infections, anisakiasis (infection by a fish parasite in presensitized individuals), streptococcal throat infections in children.

 

 

CHRONIC SPONTANEOUS URTICARIA

 

Definition

If spontaneous hives persist daily or almost daily over a period of more than 6 weeks, then chronic spontaneous urticaria is present. If the course is characterized by intermittent and not daily symptoms the urticaria is called episodic urticaria (intermittent urticaria); an IgE-mediated cause should then be excluded.

 

Epidemiology

The lifetime prevalence of chronic spontaneous urticaria is 1–2%. Usually middle-aged people (20–60 years) are affected, with females twice as frequently. In contrast to acute spontaneous urticaria, atopy is not a predisposing factor.

 

Etiopathogenesis

The causes of mast cell activation in chronic spontaneous urticaria are complex and multifactorial. IgE-mediated sensitization is extremely rarely the cause of symptoms. However, many direct and indirect factors that activate mast cells may be involved, such as autoreactive mechanisms (autoantibodies against FcεRI or IgE or unknown epitopes), infectious diseases (viral, bacterial, parasitic) – in particular Helicobacter pylori-associated gastritis, pseudo allergic reactions (to nonsteroidal anti-inflammatory drugs or food additives) and other such as psychoneurological factors or very rarely hematologic or lymphoproliferative diseases or others malignancies. It is not uncommon to find several factors in one patient.

Approximately one-third of patients with chronic spontaneous urticaria show evidence for auto reactive mechanisms through functionally mast cell-stimulating IgG antibodies against the α chain of the high affinity IgE receptor (FcεRI), rarely also against IgE itself. If the autologous serum skin test is positive, autoimmune thyroiditis with thyroid auto antibodies is more common (about 30% of patients with chronic spontaneous urticaria).

Pseudo allergens (substances that cause IgE-independent, dose-dependent mast-cell activation with an unclear mechanism without a preceding sensitization phase) like acetylsalicylic acid, other nonsteroidal anti-inflammatory drugs and as mast-cell activating drugs (histamine liberators) such as morphine, codeine, muscle relaxants, radiocontrast media, and dextran can aggravate the symptoms of urticaria and trigger exacerbations. Non-allergic hypersensitivity reactions to individual food additives such as (azo) dyes, preservatives, or antioxidants are rather rare.

A causal role of chronically persistent infections has not yet been clearly proven, but long-standing urticaria complaints often disappear after eradication of a focus (Helicobacter pylori-gastritis; streptococci or staphylococci: chronic tonsillitis, sinusitis, dental infections; persistent Yersinia enterocolitica infection; infestation with Blastocystis hominis, Giardia lamblia, Entamoeba histolytica). Best documented is the association of chronic spontaneous urticaria with Helicobacter pylori-associated gastritis. After eradication, about twice as many patients show complete or significant improvement of their urticaria compared to non-eradicated Helicobacter patients. In principle, patients with chronic spontaneous urticaria do not have infections more frequently than controls, but seem to be particularly susceptible to the development of urticaria. Potential pathomechanisms include bacteria-specific IgE, molecular mimicry of bacterial antigens with the induction of auto antibodies and permeability changes due to the inflammatory reaction.

About half of those affected also report that psychoneurological factors such as stress, especially acute stress situations, worsen the symptoms. So far, it is unclear whether the psychopathological abnormalities are primarily present or are caused reactively, for example, through a central nervous effect of histamine.

 

Clinical Features

 

The hives in chronic spontaneous urticaria are usually bright red and round with a variable diameter of one to several centimeters. In more than 50% of patients, angioedema occurs in addition to the hives, in about 30% only hives, and in 10% angioedema without hives.

Urticaria and/or angioedema can occur anytime and anywhere on the skin, most often in the evening and on the extremities. Angioedema can also occur spontaneously at night and is usually located on the head (especially the eyelids, lips, tongue), but also on the hands, feet, and genitals. Accompanying symptoms such as fever, headache, arthralgia, or gastrointestinal symptoms, but also shortness of breath, are possible. In 10% of patients, symptoms occur daily. Quality of life is significantly impaired due to severe itching, sleep disorders, and secondary psychosocial problems.

 

Differential Diagnosis

In itchy, urticarial skin lesions, differential diagnostic urticarial stages of bullous autoimmune skin diseases (especially bullous pemphigoid), scabies and other arthropod reactions, early stages of vasculitis and erythema multiforme, in pregnancy also polymorphic eruption of pregnancy or pemphigoid gestationis, must be considered.

The conceptually confusing clinical picture of urticarial dermatitis, which mostly occurs in older patients and is accompanied by plaques persisting for longer than 24 h, severe itching with partly urticarial, partly eczematous morphology, is a diagnosis by exclusion. The distribution is mostly bilateral and symmetrical on the trunk or the proximal extremities. Histology shows a predominantly dermal eczematous reaction with edema in the papillary layer, superficial perivascular infiltrate with eosinophils and minimal epidermal spongiosis. The cause can be a drug reaction or an undefined dermatitis. The epidermal involvement allows differentiation from urticaria.

In case of non-itchy hives and lack of response to H1 antihistamines, autoinflammatory syndromes with urticaria-like skin changes have to be considered for differential diagnosis. Autoinflammatory syndromes differ from autoimmune diseases in the absence of autoantibodies or autoreactive lymphocytes. Autoinflammatory syndromes are characterized by persistent or recurrent fever.

Schnitzler syndrome with arthralgia, fever attacks, monoclonal IgM-gammopathy is a non-hereditary autoinflammatory syndrome. Antagonistic antibodies against cytokines are available for some autoinflammatory syndromes (IL-1 receptor antagonist Anakinra has been successfully described in Schnitzler syndrome, IL-1β antibody Canakinumab is approved for CAPS).

 

Diagnostic Procedure

The diagnosis is based on a careful and structured history considering potential trigger factors. A complaint diary to be kept by the affected person with additional documentation of food, medication, and activities is helpful. Diagnostics encompass physical examination including dermographism, laboratory examinations, and, if necessary, additional further assessments such as consultative examinations (dental, ENT, gynecological) or imaging procedures (x-ray/computer tomography of paranasal sinuses, sonography).

Routine prick tests for inhalation and food allergens are of low diagnostic value. A biopsy is recommended if differential diagnoses are suspected (especially urticaria vasculitis, bullous pemphigoid). If physical urticaria is suspected, standardized physical tests must be carried out.

Any attempt to find a cause or trigger factor is advisable because identification and elimination is the best therapeutic strategy. This applies in particular to chronic spontaneous urticaria that has existed for more than 6 months.

It is recommended that the severity of the disease be determined on the basis of an established daily urticaria activity score (UAS), which is often determined for 7 days (UAS7).

 

Urticaria activity score (UAS)

Findings	Points
How many wheals have occurred in the last 24 h?
None	0
Few (<20)	1
Many (21–50 hives)	2
Very many (≥50 hives or large confluent areas)	3
How strong has the itching been in the last 24 h?
No itching	0
Mild (present but not annoying or troublesome)	1
Moderate (troublesome but does not interfere with normal daily activity or sleep)	2
Intense (severe pruritus, which is sufficiently troublesome to interfere with normal daily activity or sleep)	3
Urticaria activity score (UAS) of 1 day	Sum of points (0–6)
UAS7 = Total score for a week (maximum 42 points)

 

Another new system, which has been established and validated in recent years, has proven to be particularly practical: Urticaria Control Test (UCT). This is suitable for assessing disease activity of the last 4 weeks of all patients with chronic urticaria (CSU and CINDU) and for monitoring therapy decisions through standardized and reliable documentation. The UCT consists of four questions, each with five possible answers. The higher the score, the better under control the urticaria is. Good control can be assumed from a cut-off value of 12 points. If the value is less than 12, treatment should be optimized.

 

Urticaria Control Test (UCT)

Question	Reply	Points
1. How much have you suffered from the physical symptoms of the urticaria (itch, hives and/or swelling) in the last 4 weeks?	Very much Much Somewhat A little Not at all	0 1 2 3 4
2. How much was your quality of life affected by the urticaria in the last 4 weeks?	Very much Much Somewhat A little Not at all	0 1 2 3 4
3. How often was the treatment for your urticaria in the last 4 weeks not enough to control your urticaria symptoms?	Very often Often Sometimes Seldom Not at all	0 1 2 3 4
4. Overall, how well have you had your urticaria under control in the last 4 weeks?	Not at all A little Somewhat Well Very well	0 1 2 3 4

Cut-off value 12 points or higher: Good control can be assumed

Cut-off values <12: urticaria is not controlled, treatment should be adapted

Routinely laboratory determination of only a differential blood count as well as of erythrocyte sedimentation rate or C-reactive protein as a coarse grid on inflammatory/infectious processes is recommended. Further diagnosis depends on patient history as well as the clinical picture.

 

Proven diagnostics procedures for chronic spontaneous urticaria

Examination for	In detail	Method	Remark
Infection	General information	Differential blood count C-reactive protein or erythrocyte sedimentation rate
	Helicobacter pylori	Monoclonal stool antigen test or C-urea breath test or histopathology	The non-invasive monoclonal stool antigen test is very sensitive; observe waiting periods for taking antacids and proton pump inhibitors as well as antibiotics Serology is not reliable
	Streptococci	Anti-DNaseB titer, Anti-Streptolysin titer (throat swab)
	Staphylococci	Anti-Staphylolysin Titer
	Yersinia enterocolitica	Yersinia serology (IgA, IgG, immunoblot)	IgA and several bands in immunoblot indicate persistent yersiniosis
Autoreactive	Autoimmune thyroiditis	Basal TSH Thyroperoxidase antibodies Thyroglobulin antibodies TSH-receptor autoantibodies	If basal TSH is abnormal, FT3 and FT4 should be assessed.
	FcεRI (IgE), serum factor(s)	Autologous serum test	Direct Anti-FcεRI autoantibody assay are not commercially available. Serum functional tests such as histamine release, leukotriene production, CD63 or CD203c expression are too complex in routine.
Pseudoallergy	Nonsteroidal anti-inflammatory drugs	Anamnesis, avoidance	Alternatives: paracetamol, tramadol, etoricoxib; oral provocation test at urticaria free intervals, if necessary
	Food additives	Standardized low pseudo allergen diet for 4 weeks	If applicable, blinded oral provocation test with pseudo allergen-rich food, collective additives, exposure

 

Other possible diagnostic measures that are not routinely required are:

·        Antinuclear antibodies (preferably in urticaria vasculitis to exclude lupus erythematosus)

·        Stool on worm eggs (eosinophilia, increased total IgE, suspected parasitosis)

·        Biopsy (e.g., of lesions that persist in loco for more than 24 h, for differential diagnosis of urticaria vasculitis, urticarial dermatitis, bullous pemphigoid, cutaneous mastocytosis)

·        Basal serum tryptase (to differentiate mastocytosis)

·        Specific IgE antibodies (if IgE-mediated mechanisms are suspected)

The most common test for determining autoreactivity is the autologous serum test since commercially available tests for the determination of auto antibodies against IgE or FcεRI are not available and functional tests (histamine release test, sulfide-leukotriene production or flow cytometric determination of activation markers such as CD63 on basophils) are reserved for specialized centers within the scope of studies due to the logistical effort involved. The result is currently only used to subclassify chronic spontaneous urticaria into autoreactive and non-autoreactive. A therapeutic consequence has not yet been established.

 

In the case of inconspicuous basic diagnostics, an outpatient 4-week standardized low-pseudo allergen diet may be tried under qualified nutritional consultation. If there is a significant improvement in symptoms, an inpatient provocation test with standardized pseudo allergen-rich food, collective exposure to food additives, and individual substance breakdown should be considered. Overall, about one-third of the patients benefit from the diet, but complete freedom from symptoms is rarely achieved and a subsequent provocation test is rarely conspicuous. After 3–6 months of a strict pseudo allergen-low diet, most patients will be able to tolerate the gradual intake of food again.

 

Course

 

Chronic spontaneous urticaria persists on average for 3–5 years; only half of those affected show remission within 10 years.

 

Therapy

The aim of the therapy is complete freedom from symptoms. Strategies include elimination or avoidance of the trigger (e.g., eradication of Helicobacter pylori), inhibition of mediator release from mast cells (glucocorticoids, phototherapy, cyclosporin A), and inhibition of mediator action at the target organ (H1 antihistamines, leukotriene receptor antagonists).

General Recommendations for Urticaria

·        Elimination of causal factors

·        Avoidance of nonsteroidal anti-inflammatory drugs (acetylsalicylic acid) or mast cell-activating drugs

·        Avoidance of ACE inhibitors, AT-II receptor antagonists (only in recurrent angioedema)

·        Avoiding overheating, alcohol, stress

·        Topical antipruritic treatment (polidocanol 3–5%), cooling lotions

·        In case of threatening angioedema, anaphylaxis: carry emergency medication with you.

In addition to avoiding nonspecific activating factors, identified persistent bacterial (Helicobacter pylori infection) or parasitic infections should be treated, as this can lead to complete freedom from symptoms. The success of the therapy should be investigated (antibiotic resistance of Helicobacter pylori is known). Urticaria often only responds after a delay of 8–12 weeks of eradication therapy. For thyroid auto antibodies, therapy may be indicated for thyroid dysfunction, but has no effect on urticaria. In case of improvement under a low pseudo allergen diet a gradual relaxing of the diet after 3–6 months can be tried. A specific therapy in case of a positive autologous serum test and/or the presence of auto antibodies against FcεRI is not yet available.

Topical treatment is not very effective, but is often used by some patients in addition to systemic therapy. Suitable products are itch-relieving and cooling substances, for example polidocanol-containing (3–5%) lotions or creams. Topical antihistamines are not recommended due to their sensitizing potential.

Symptomatic standard therapy for the first stage consists of non-sedating or less-sedating histamines due to the central importance of histamine. H1 antihistamines (in alphabetical order) are: bilastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine and loratadine, in standard dosage. There have not been many direct comparative studies of chronic urticaria between these H1 antihistamines. In the two studies in which a comparison of desloratadine with levocetirizine was investigated, levocetirizine performed better.

They block the histamine effect at the H1 receptor and thus stop itching, erythema, and wheals. Taken regularly and, if necessary, spread over the day is more effective than taken as needed. Older H1 antihistamines (e.g., hydroxyzine) should only be used if sedation is expressly desired, especially due to the usually required dose increase. Their negative influence on the REM sleep phase, learning, and mental performance must be taken into account.

 

Recommended four-stage symptomatic treatment algorithm according to evidence and consensus 

 

·        Stage one:

·        Standard dose of second-generation H1 antihistamine

·        If inadequate control: after 2–4 weeks or earlier, → stage 2

·        If symptoms are intolerable → stage 2

·        Stage two:

·        Dosage increase of the second-generation H1 antihistamine up to fourfold (off-label)

·        If inadequate control: After 2–4 weeks or earlier, if symptoms are intolerable → stage 3

·        Stage 3 (in addition to stage 2):

·        Add omalizumab

·        If inadequate control: Within 6 months or earlier, if symptoms are intolerable → stage 4

·        Stage 4 (in addition to stage 2):

·        Add cyclosporin A

·        In exacerbations systemic glucocorticoids are possible for a short time (maximum 10 days).

·        Stages 3 and 4 should be performed under the supervision of a specialist

With the standard dose of H1 antihistamines and also with a dose increase of up to four times (off-label) complete freedom from symptoms can only be achieved for a small number of patients.

If there is no response to the standard dosage within 2 weeks, the second stage with an up to fourfold increase in dosage (off-label use) taking into account potential side effects is recommended. Due to the individual responses, a change to another H1 antihistamine should also be considered.

In case of further therapy resistance within the next 2–4 weeks, treatment is progressed to the third stage as add-on therapy to the second stage using omalizumab.

If within 6 months or earlier, if symptoms are intolerable, and omalizumab add-on is not effective, stage four cyclosporin A (off-label, dose 2.5–5 mg/kg body weight per day, response within 4–6 weeks) should be added to second generation H1 antihistamines (stage 2)

The risk-benefit profile should be carefully weighed against other off-label alternatives (dapsone, montelukast, H2 antihistamines) due to the low level of evidence.

Omalizumab has been approved for the indication of chronic spontaneous urticaria that does not respond to antihistamines. About half of patients with chronic spontaneous urticaria respond after only two injections (mean time to response 6 weeks). However, some patients (about 15%) need more than 6 months until urticaria symptoms are controlled. Casuistically, in case series and for some subtypes such as cholinergic urticaria, double-blind controlled trials have demonstrated efficacy with omalizumab in chronic inducible urticaria. After weaning from omalizumab, however, a relapse usually occurs just as quickly, so it is a symptomatic therapy. The mechanism of action of omalizumab (anti-IgE antibody) is still unknown. The rapid success speaks against a down-regulation of high-affinity IgE receptors on mast cells. The hypothesis that anti-IgE treatment captures IgE autoantibodies have not been proven so far. Recently, a randomized phase II clinical trial has demonstrated safety and efficacy of ligelizumab, an anti-IgE antibody with increased affinity to the IgE-receptor, compared to placebo and omalizumab in chronic spontaneous urticaria.

For cyclosporin A evidence for efficacy and safety in the indication H1 antihistamine-resistant chronic urticaria is available from randomized controlled trials. H2 antihistamines were investigated only in combination with sedating H1 antihistamines in studies with contradictory results. Dapsone may be more suitable for pronounced inflammatory infiltrates with neutrophils and/or eosinophils (pressure-associated chronic spontaneous urticaria or delayed-pressure urticaria). Other therapies successful in smaller studies or individual cases are (hydroxy)chloroquine, sulfasalazine, tacrolimus, methotrexate, mycophenolate mofetil, cyclophosphamide, and photo treatment with UVB 311 nm.

 

Systemic glucocorticoids should be used for a maximum of 10 days for acute exacerbations; the initial recommended daily dose is 0.5–1 mg/kg body weight prednisolone equivalent. There should be regular checks every 3–6 months to see whether it is possible to reduce the dose or discontinue medication if spontaneous remission has occurred.

 

Chronic Spontaneous Urticaria in Childhood

Chronic spontaneous urticaria in childhood is less common than in adults. The diagnostic procedure as well as the therapy of chronic spontaneous urticaria in childhood does not differ from those in adults. Trigger factors are comparable, with persistent streptococcal infections being most common. As with adults, one-third has a positive autologous serum test. A weight-adapted dose increase of modern H1 antihistamines is also recommended for children who do not respond to the standard dose. Omalizumab is approved for the indication of chronic spontaneous urticaria from the age of 12 years. Alternatives such as montelukast and cyclosporin A are generally approved in childhood.

 

Causes of chronic urticaria:

Autoimmune represents those patients with functional autoantibodies against FcϵRI or the Fc portion of IgE.

 

Chronic spontaneous urticaria

 

Idiopathic

 

At least 50% of patients with chronic spontaneous urticaria are idiopathic.

Allergy

 

IgE‐mediated allergy is probably never the cause of chronic spontaneous urticarial.

 

Autoimmune

 

Patients with autoimmune urticarial who have functional autoantibodies are more likely to respond to immunosuppressive therapies.

 

The pathogenesis of autoimmune urticarial and the proposed mechanism of action of omalizumab for autoimmune urticaria.

 

Pseudo allergy

 

Food additives, natural salicylates, amines, spices, green teas and alcohol may aggravate existing chronic spontaneous urticaria in up to 30% of patients but are rarely the cause. A 3‐week trial of a low pseudo allergen diet may be considered as a diagnostic investigation in well‐motivated patients.

 

Infections and infestations

 

Bacterial infections, such as dental sepsis, sinusitis, urinary tract and gallbladder infections, may be associated with chronic urticaria. If present, treatment of the infection usually does not cure urticaria. Helicobacter pylori infection of the stomach has been associated with chronic spontaneous urticaria.

 

Duration of Hives

Type of Urticaria	Duration
Spontaneous and delayed pressure	4-36 hours
Physical (except delayed pressure)	30 min-2 hours
Contact (may have a delayed phase)	1-2 hours
Urticarial vasculitis	1-7 days

 

 

Aggravating factors

 

Even though a specific cause of urticaria may not be identified in individual patients, it is often possible to identify non‐specific aggravating factors in chronic urticaria, such as heat and clothing pressure in spontaneous urticaria, avoidance of which can help to minimize exacerbations.

 

Aggravating factors for spontaneous urticaria

·        Physical

o   Pressure

o   Overheating (passive or active)

·        Infections, e.g. upper respiratory tract infections

·        Drugs

o   Non‐steroidal anti‐inflammatory drugs (common)

o   Opiates (rarely)

·        Dietary pseudo allergens

o   Natural salicylates

o   Histamine

o   Food additives

o   Spices

o   Alcohol

·        Menses (premenstrual especially)

·        Stress

 

Pressure and heat

Patients often volunteer that weals come up below tight clothing or after overheating.

 

Drugs

Aspirin and other related non‐steroidal anti‐inflammatory drugs (NSAIDs), such as diclofenac, can aggravate urticaria by non‐allergic mechanisms.

 

Dietary pseudo allergens

The most frequently implicated food additives are tartrazine (E102) and other azo dyes, including sunset yellow (E110).

 

Infections

Chronic urticaria is frequently exacerbated by intercurrent viral infections. This may be a non‐specific effect of circulating pro‐inflammatory cytokines or chemokines.

 

Menstrual cycle and pregnancy

Urticaria may worsen premenstrually, but if urticaria occurs predominantly or only premenstrually, it has been attributed to progesterone sensitivity.

 

Stress

Flare‐ups of urticaria do occur at times of psychological stress.

 

 

Inducible Urticarias

The inducible urticarias represent a distinct subgroup of the urticarias that are induced by an exogenous physical stimulus rather than occurring spontaneously. These include physical forms of urticaria triggered by external mechanical stimulation, such as pressure, cold, heat, and special forms (contact urticaria, cholinergic urticaria and aquagenic urticaria). Exercise-induced urticaria/anaphylaxis is mostly associated with an IgE-mediated allergy to food (mostly wheat, rarely shellfish or others), and is therefore classified as food allergy or anaphylaxis and no longer as chronically inducible urticaria.

The physical urticarias are classified by the predominant stimulus that triggers whealing, angioedema or anaphylaxis. Of all the urticarias, delayed pressure urticaria and cholinergic urticaria may affect the quality of life most severely. While the lesions of most physical urticarias occur within minutes of provocation and generally resolve within 2 hours, a few physical urticarias (e.g. delayed pressure urticaria, delayed dermographism) develop after a delay of several hours and persist for 24 hours or longer.

The weals are usually localized to the stimulated area of skin. However, sometimes the physical stimuli need to produce a systemic effect, e.g. a rise or drop in core body temperature, to induce urticaria of a reflex type. Thus, generalized heating of the body can induce cholinergic urticaria (which is common), and generalized cooling, cold reflex urticaria (which is rare). Here, multiple small wheals occur on widespread areas of the body.

Angioedema may be seen with all the physical urticarias except with symptomatic dermographism. Vibratory angioedema manifests with subcutaneous swellings but not wheals. Also, several forms of physical urticaria can coexist in the same patient. Common combinations include: (1) symptomatic dermographism and cholinergic urticaria; (2) cold and cholinergic urticaria; and (3) delayed pressure urticaria and delayed dermographism. Delayed pressure urticaria may also coexist with chronic urticaria.

Most chronic inducible urticaria forms persist for 3–5 years or longer.

Diagnosis is made through careful history, clinical examination, and standardized physical testing.

 

 

Dermographism

 

After light, linear striation of the skin with a hard object (wooden spatula, pin), the touched area reddens in a line within 15–20 s due to reflective vasodilation: red dermographism (Dermographismus ruber). In patients with atopic diathesis or atopic diseases, however, vasoconstriction often results in white dermographism (Dermographism albus). In atopic eczema, white dermographism is one of the minor diagnostic criteria.

This is divided into simple or symptomatic. 

 

An urticarial reaction occurs within 5 min in the contact area and slightly beyond without itching, which can last for minutes to more than 1 h. in response to moderate stroking of the skin and may be regarded as an exaggerated physiologic response. This asymptomatic Simple immediate urticarial dermographism has no disease value and occurs in about 5% of the population. The very rare urticarial late dermographism develops only after 3–6 h and can last up to 24 h.

 

Symptomatic immediate dermographism is the most common type of physical urticaria. It manifests as linear wheals at sites of scratching or sites of friction, such as collars and cuffs of clothes. Whealing occurs after gentle stroking of the skin in response to a shearing force. Patients, most frequently young adults, often complain of pruritus before the wheals appear and may not associate them with scratching. The itching is often disproportionately severe compared with wealing, is worst in the evening and often occurs in bouts. The lesions usually resolve within an hour. Mucosal involvement does not occur, but vulvar swelling during sexual intercourse has been reported. As a rule, the hives are not round, but arranged in a line or stripe according to the stimulus (writing on the skin is possible). Since wheals caused by rubbing can cause itching again, a vicious cycle is triggered. The general course is unpredictable, but usually there is a gradual tendency towards improvement over several years. Symptomatic dermographism is usually idiopathic, but occasionally follows scabies infestation and penicillin allergy. There is no association with systemic disease, atopy, food allergy, or autoimmunity. Similar to an urticarial late dermographism, a delayed and long-lasting symptomatic dermographism can also occur.

Symptomatic dermographism lasts an average of 6.5 years. Chronic spontaneous urticaria or another inducible urticaria is often found in combination.

Symptomatic dermographism is most easily diagnosed by using a calibrated instrument, the dermographometer, which has a spring-loaded stylus, the pressure of which can be adjusted to a predetermined setting. Stroking the skin at a tip pressure of less than 36 g/mm2 induces a linear, itching weal within 10 min.

Treatment of symptomatic immediate dermographism with low-sedating H1 antihistamines is often effective, sometimes in low doses.

 

Delayed pressure urticaria

Delayed pressure urticaria (DPU) is important because it can interfere severely with quality of life and its treatment is difficult. Delayed pressure urticaria is uncommon (2% of urticarias). Up to 37% of patients with chronic spontaneous urticaria have associated DPU. Conversely, nearly all patients with DPU have associated spontaneous wheals. Because of this association and the delayed onset, patients may not be aware of any relationship to pressure unless specifically questioned.

Wealing occurs at sites of sustained vertical pressure applied to the skin after a delay of 30 min to 9 h, but usually 4–8 h, and lasts 12–72 h; sometimes it resembles angioedema. These deep swellings may be itchy, but are often tender or painful.

Sites frequently involved are the waistline after wearing tight clothing, below the elastic of socks, on the buttocks and lower back after sitting, the feet in tight shoes, the palms after manual work, the soles after walking or climbing ladders, and the genitalia after intercourse.

DPU may be accompanied by systemic symptoms of malaise, flu-like symptoms, arthralgia and myalgia. The condition may be mistaken for urticarial vasculitis.

The diagnosis can usually be made by careful questioning and confirmed by testing. Objective testing is performed by using rods with a convex end diameter of 1.5 cm weighted with 2.5 kg for 20 min or 4.5 kg for 15 min on the back or thighs. A positive response is when indurated lesions are present at test sites at 6 h. Areas of delayed pressure urticaria may be refractory to further pressure-induced lesions for up to 48 h.

The average duration of delayed pressure urticaria is 6–9 years.

 

The differential diagnosis is a pressure-aggravated chronic spontaneous urticaria in which whealing occurs not only spontaneously but is also pressure-associated (mostly in pressure-loaded areas, or the belt area). The wheals often only appear after 30 min in the pressure test, but are not delayed for several hours.

 

Histopathology

In delayed-pressure urticaria, a biopsy from a pressure-induced wheal may be useful. The infiltrate is more pronounced than in other forms of urticaria; histopathologically a differentiation from urticaria vasculitis is possible. Early lesions (<5 h) are dominated by neutrophils and eosinophils, late lesions (>12 h) are more likely to have lymphocytes and eosinophils. The underlying swellings are also considered histamine-mediated, whereby the expression of adhesion molecules on endothelial cells and the neutrophil- and eosinophil-rich infiltrate indicate a role of cytokines.

As far as possible, vertical pressure should be avoided (by padding the affected area).

Delayed pressure urticaria responds poorly to H1 antihistamines but higher than licensed doses of cetirizine (10 mg three times a day) have been used, as it also inhibits eosinophil migration. Some patients benefit from additional administration of medium to low doses of glucocorticoids (40–20 mg prednisolone equivalent or less). Drugs that inhibit granulocyte infiltration (including colchicine, dapsone and sulphasalazine) may be helpful although supporting clinical studies are lacking. Dapsone (50–150 mg daily, 6 days per week) has been described in case series as being successful. Further options are methotrexate (15 mg/week), montelukast (10 mg/day), sulfasalazine (up to 3 g/day). The use of topical clobetasol propionate 0.5% under occlusion for the hands and feet may be effective and wearing comfortable shoes or insoles can be useful. Omalizumab has also been described as successful in individual cases.

 

Cholinergic urticaria (sweating induced)

It accounts for about 5% of urticaria. Small weals begin within 15 minutes after the patient experiences a general overheating of the body as a result of sweat-inducing stimuli, whether induced by a rise in core temperature, emotion or gustatory stimuli, such as any form of physical exertion, hot baths or sudden emotional stress, moving from a cold to a hot room, drinking alcohol and eating spicy food. It occurs more frequently in adolescents and young adults with an atopic diathesis and may be worse in the winter months and is unusual in the elderly.

After the appropriate stimulus, pruritus is followed by the development of multiple, small, 2- to 3-mm dome-shaped monomorphic wheals with a pale center and surrounded by obvious erythematous flare that are symmetrically distributed. They are most prominent on the upper half of the body such as face and trunk but can also affect the lower legs and forearms and even become generalized. Oblique lighting is helpful for observing the weals, especially in dark skin. The lesions persist for a few minutes to an hour or two. Angioedema and systemic manifestations consisting of faintness, headache, palpitations, abdominal pain, and wheezing may occur.

Cold urticaria, symptomatic dermographism, or aquagenic urticaria may be associated with cholinergic urticaria. There is usually a gradual tendency towards improvement, but the condition may last for years. Rarer forms include cholinergic pruritus, cholinergic erythema (in which pruritic, symmetric, small erythematous macules appear to be persistent, but individual lesions actually last for up to 1 hour), and cholinergic dermographism. Severe exercise-induced cholinergic urticaria may sometimes progress to anaphylaxis.

 

The most reliable and efficient testing method is to ask the patient to run in place or to use an exercise bicycle for 15 minutes, and then to observe the patient for 1 hour to detect the typical micropapular hives. Exercise testing should be done in a controlled environment. Patient is asked to take a hot bath at 40-42°C for 15 min to raise the core temperature by 0.7 to 1°C—and induce characteristic micropapular hives. A few patients find that if they can bring on a severe attack by suitable exertion they can achieve freedom for up to 24 h afterwards, analogous to temporary desensitization.

If wheals only occur with bathing, an aquagenic urticaria or a heat urticaria should be considered. If, on the other hand, only the exercise test is positive, exercise-induced urticaria (e.g., wheat-dependent exercise-induced urticaria/anaphylaxis) must be ruled out.

Therapeutically, modern H1 antihistamines (possibly off-label in increased dosage) are used prophylactically regularly or 30–60 min before typical situations. Not infrequently, symptoms are only partially suppressed by this. Tolerance induction for physical exertion is difficult to achieve. Omalizumab has been shown to be effective in a randomized double-blind controlled trial. Optional drugs with low evidence levels include ketotifen, danazol, H2 antihistamines, montelukast, doxepin, β-blockers, or prednisolone.

The average duration of cholinergic urticaria is 7.5 years. Progressions over 30 years have been described.

 

Primary cold contact urticaria

 

 

This is by far the commonest form, occurring at any age but most frequently in young adults. Although It may be preceded by non‐specific upper respiratory tract viral infections, arthropod bites or stings, the cause of most cases remains unknown (idiopathic). Itching and wealing occur in cold-exposed areas after contact with cold objects, cold water or cold air within minutes of rewarming the skin after cold exposure and last up to 1 h. Cold winds and cold rain are particularly effective stimuli. Sometimes, the mouth and pharynx may swell after drinking cold liquids. Systemic symptoms of flushing, headache, syncope, and abdominal pain can develop if large areas are affected. Cold baths and swimming should usually be avoided as there is a potential risk of anaphylaxis.

 

The mean duration of cold urticaria is 5–10 years, though primary cold contact urticaria may be more transient if it follows a viral infection.

Diagnosis is made by application of a melting ice cube in a thin plastic bag onto the skin for 5–20 min, and wealing occurs within 10 min, usually during rewarming.

 

A distinction is made between primary, acquired cold urticaria (an allergic type I reaction) and secondary cold urticaria with detection of cold-sensitive serum proteins (cryoglobulins, cold agglutinins, cryofibrinogen) in about 2% of those affected, possibly in the context of malignant lymphoma or leukaemia or in the case of infectious disease (borreliosis, HIV infection/AIDS, infectious mononucleosis).

To exclude secondary cold urticaria in infectious triggers such as borreliosis, infectious mononucleosis, and HIV infection, serological tests should be performed, as well as tests for cryoglobulins, cold agglutinins, and cryofibrinogen.

H1 antihistamines of the newer generation are the therapy of first choice (if a standard dose is not effective increased doses up to fourfold, off-label, should be tried). Whether the prophylactic administration of H1 antihistamine can suppress potentially life-threatening systemic symptoms has not yet been investigated. Therefore, patients with severe cold urticaria should be urgently advised to avoid the triggers and receive an emergency kit including an epinephrine autoinjector.

Tolerance induction by increasing cold exposure (multiple daily showers) can be successful, but is not harmless and usually not permanently practicable.

 

 

Contact Urticaria

Contact urticaria is characterized by a wheal-and-flare response that occurs within 30 to 60 minutes after contact with intact skin or mucosa to certain agents, but contact erythema and even burning and stinging without erythema are sometimes embraced in the definition. Percutaneous or mucosal penetration of the urticant may have distant effects, including acute urticaria or even anaphylaxis. There are nonimmunologic and immunologic forms.

Stages of progression in contact urticaria

Stage	Description
1	Localized reaction (redness and swelling) with nonspecific symptoms (burning, itching, tingling)
2	Generalized reaction
3	Extracutaneous symptoms (rhinoconjunctivitis, orolaryngeal and gastrointestinal dysfunction)
4	Anaphylactic shock

Pathophysiology of contact urticaria

Nonimmunological contact urticaria is the most common type and most benign occurring without prior exposure to an eliciting substance. Percutaneous microinjection of histamine, acetylcholine, and/or serotonin by plants (e.g. nettle stings) or animals (e.g. caterpillars, jellyfish) as well as contact with histamine liberators that degranulate mast cells (e.g. dimethyl sulfoxide, cobalt chloride) can result in contact urticaria. A more common form is from exposure to either sorbic acid and benzoic acid in eye solutions and foods such as tomato ketchup or cinnamic aldehyde and balsam of Peru in cosmetics; the reaction is mediated by prostaglandin D₂ formation in the epidermis rather than histamine release from the mast cells, so there is lack of response to antihistamines and the positive response to non-steroidal anti-inflammatory drugs (NSAIDS).  An occupational exposure includes ammonium per sulphate in hairdressing.

The reaction may take up to 45 min to develop and remain up to 24 hours. This type of urticaria generally does not go beyond the localized reaction described in Stage 1, presenting with redness and swelling along with nonspecific symptoms of burning and itching.

The release of histamine is the major mechanism of action seen in immunological urticaria. The pathophysiology of immunological CU differs from nonimmunological CU, as it occurs due to the production of allergen-specific IgE following prior sensitization to a causative agent. After the initial binding of allergen-bound IgE to mast cells, histamine is released resulting in an immediate, localized weal and flare resolving within 2 h, and progress to generalized urticaria, or even anaphylaxis if the individual is extremely hypersensitive.

Allergic contact urticaria can be seen in children with atopic dermatitis who become sensitized to environmental allergens. The commonest causes are foods (for example, nuts, fish, fruits) or latex. Latex is present as latex proteins in rubber agents such as gloves, condoms, and urinary catheters. Thus, occupations with the maximum exposure to latex products are more likely to develop immunological CU, including healthcare or dental workers.

The oral allergy syndrome is a form of allergic contact urticaria that presents with itching and mild swelling of the mouth (lips, tongue, palate and throat), sometimes associated with other allergic features such as rhino conjunctivitis and asthma, within minutes of eating fresh fruits such as apples, pears, peaches and cherries, but not cooked, dried, peeled or bottled fruit. It usually occurs in hay-fever sufferers and represents a cross-reaction between pan allergens in grass or birch pollens with fruit proteins. Angioedema and anaphylaxis are fortunately very rare.

Oral allergy syndrome may respond to antihistamines or to a sympathomimetic agent such as ephedrine taken by mouth.

 

Treatment of contact urticaria

Emphasis for treatment of CU should be placed on prevention–thorough history taking and appropriate clinical testing will help determine the problematic materials. Once the diagnosis of contact urticaria is made, avoidance is almost always possible. In case of contact, patients should carry antihistamines and receive education on self-administration of subcutaneous epinephrine.

Because contact with an eliciting substance may still occur, management is divided into first-, second-, and third-line therapies. In addition to patient education, first-line therapy includes the use of H1 receptor antihistamines. The ability of these agents to suppress the histamine-induced wheal-and-flare response has been well studied in urticaria they may decrease both the number and the duration of wheals. H2 receptor antagonists, including ranitidine and famotidine, are often used along with H1 receptor antagonists, because 15% of the skin receptors are of the H2 type. The improved tolerability of newer, nonsedating antihistamines may give them a clear advantage over older antihistamines and corticosteroids.

 

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF URTICARIA

The differential diagnosis of urticaria includes all dermatologic conditions with an urticarial component, including insect bite reactions (popular urticaria), pre-bullous phase of pemphigoid (i.e. urticarial pemphigoid), acute eyelid contact dermatitis (versus angioedema), urticarial drug reactions (e.g. antibiotics), and the urtication that may occur when lesions of urticaria pigmentosa are rubbed. In all these conditions, the urticarial component is part of a more prolonged inflammatory process (or mast cell proliferation in the case of mastocytosis) than in true urticaria and should be readily distinguishable by the prolonged duration of individual lesions. Especially in young children, urticaria may develop a dusky center and be confused with erythema multiforme.

 

Diagnosis

Clinical history taking and diagnosis

A comprehensive history is essential in every patient with urticaria. It should cover the duration of disease, frequency of attacks, duration of individual lesions, associated illness, previous treatment, known adverse reactions, past and family history, occupation and leisure activities, and an assessment of the impact of the disease on the patient’s quality of life. A full physical examination looking for the morphology and duration (by circling individual lesions) of wheals, purpura, and signs of systemic disease should always be undertaken, but it is often normal. Weals lasting more than 24–48 h, particularly if painful or tender, suggest the possibility of urticarial vasculitis or delayed pressure urticaria, but can occur in spontaneous urticaria. Purpura, although rarely seen, suggests urticarial vasculitis, but can occur in spontaneous urticaria in severe cases.  The occurrence of angioedema should be noted, particularly if it has affected the oropharynx with difficulty in swallowing or breathing. Enquiry should be made for systemic symptoms sometimes associated with cutaneous lesions, including malaise, headache, abdominal pain, arthralgia, wheezing and syncope. Possible precipitating or aggravating factors—including physical factors such as heat, cold, localized pressure on the skin, friction and sunlight—should be sought directly. It is important to ask about any association with recent acute infection, drugs, non-prescription medicines and foods, although the latter are rarely a cause for chronic urticaria. A family history of atopy, autoimmunity or angioedema may be useful information.

Investigation should be targeted at specific features identified in the clinical assessment, and may include blood tests, skin biopsy (obtained in all patients with lesions lasting more than 24 hours), challenges for physical urticarias, food additives and drugs, and, infrequently as an extended investigation, skin tests for allergy and measurement of histamine-releasing auto antibodies. Most patients with antihistamine-responsive urticaria do not need an extensive investigation.

 

 

Investigation of urticaria

Acute urticaria

Usually none, except where suggested by the history 

·        Infection

o   Throat swab if pharyngeal symptoms

o   Other appropriate samples for suspected viral or bacterial infection

·        Drugs

o   Withdraw suspected drugs

·        Foods

o   Investigate for IgE sensitization (skin prick tests or Immuno CAP where appropriate)

Episodic urticaria

      -Pseudoallergy challenge capsules (if available) 

               -Food additives 

              -Non-steroidal antiinflammatory drugs

Chronic urticaria

    Physical challenge provocation tests (where suggested by the history)   

    Blood tests (spontaneous urticaria, if unresponsive to H1-antihistamines)   

            FBC, ESR, thyroid antibodies, thyroid function tests 

§  C4 complement (angioedema without weals)

§  Non‐organ specific auto antibodies (if associated autoimmune disease possible)

§  Autologous serum skin test (where facilities are available) 

§  Basophil histamine release assay or basophil activation tests (if functional autoantibodies suspected)

§  Helicobacter pylori (stool antigen or urea breath test) (if peptic ulcer symptoms)

§  Stool for ova, cysts and parasites (foreign travel)

§  Chest X‐ray (if lymphoma considered)

§  Others: as determined by the history and physical examination

§  3‐week trial of a low pseudo allergen diet

§  Skin biopsy (12–16 h old lesions, if urticarial vasculitis suspected)

Acute urticaria

IgE-mediated reactions to environmental allergens as a cause of acute urticaria and contact urticaria can be confirmed by skin prick testing and serum radioallergosorbent tests (RAST). Results of both have to be interpreted in the clinical context.

Chronic urticaria

No investigations are routinely required for the majority of patients with mild disease that responds to antihistamines. A useful screening profile for non-responders with more severe disease could include a complete blood count and erythrocyte sedimentation rate (ESR). An elevated ESR suggests the possibility of an underlying systemic disease (lupus erythematosus, urticarial vasculitis), and an eosinophilia would prompt a search for parasitic disease. Thyroid function tests and thyroid auto antibodies should be performed, if indicated clinically, as around 14% of patients with chronic ordinary urticaria may have thyroid autoimmunity and may be an indicator of autoimmune urticaria. Initial reports suggest that treatment with thyroxine to suppress thyroid activity may resolve the urticaria. Tests for bowel parasites may be considered in the appropriate clinical setting.

If angioedema is a major component of the disease, measuring plasma C4 complement should be performed as a screening test for hereditary or acquired C1 esterase inhibitor deficiency.

A skin biopsy may be helpful if the weals persist for more than 48 h and do not respond to antihistamines. Urticarial vasculitis or delayed pressure urticaria is then suspected.

The term “autoimmune” urticaria is increasingly being used for patients with evidence of functional serum auto antibodies. Demonstration of autoreactivity in the form of a localized wheal and flare response to intradermal injection of autologous serum (the autologous serum skin test; ASST) provides useful evidence of functional factors in the blood, but is not specifically a test for auto antibodies. A negative test, however, has very good negative predictive value for the absence of functional antibodies.

 

Autologous serum skin test (ASST): At 30 minutes, a red wheal response is present at the site of an intradermal injection of autologous serum, but not at that of a normal saline control. For the test to be positive, the wheal response at the serum injection site must be at least 1.5 mm greater in diameter than the control site. The ASST is a reasonably sensitive and specific screening test for functional auto antibodies as detected by the basophil release assay.

Immunoassays for anti-FcεRI and anti-IgE antibodies (commercially available) have been detected by Western blot and ELISA. There is overlap between: (1) autoreactivity; (2) functional auto antibodies as detected via basophil or mast cell assays; and (3) immunoassays (“immunoreactivity”). The strongest evidence for an autoimmune etiology of urticaria is provided by demonstrating all three features, but many clinicians would accept a positive ASST and/or a positive functional assay as providing sufficient proof of autoimmunity to guide therapies and prognosis.

Attention should be paid to medication, especially NSAIDs. Patients frequently suspect allergy to foods, but this is rarely if ever found in adults with chronic ordinary urticaria. A food diary may be helpful, especially in episodic urticaria, but it should be remembered that the time interval may vary from a few seconds with allergy and up to 24 h with dietary pseudo allergens, and the substance may have been consumed regularly for years. If the patient suspects food additives, or if they have improved substantially on elimination of the substance or on a diet free of food additives, challenge testing can be carried out on a placebo-controlled basis. This is performed when the patient is in relative remission, and antihistamine therapy need not be stopped, although this is desirable. The most important test substances are tartrazine (E102), aspirin, sodium benzoate (E211) and 4-hydroxybenzoate (E214–219). The patient records any urticarial response, and if present the suspected substance should be re-administered on at least one occasion for confirmation of the results. When the provocation tests are positive, a tartrazine-free, salicylate-free or other appropriate diet can be suggested and is usually only necessary for a few months. It is usually inappropriate to carry out provocation tests in patients who respond well to antihistamines. A low-pseudo allergen diet may be helpful for some patients, especially if antihistamines have failed or are not accepted.

 

MANAGEMENT OF URTICARIA

 

Patients should be given advice and information on common precipitants, treatments, and prognosis.  Non-specific measures including the wearing of loose fitting clothing and application of soothing creams with menthol may be helpful. Patients should minimize aggravating factors including overheating, stress and alcohol. Aspirin and aspirin-containing compounds, other NSAIDs, and also opiates, should be avoided if possible. Paracetamol is usually a satisfactory alternative. Selective COX-2 inhibitors may be tolerated by aspirin sensitive patients if an antiinflammatory drug is essential. If food additives, colorings or preservatives have been proven to be a problem, diets excluding these substances may be of value to a limited number of patients. Drug therapies can be first, second, or third-line.

 

First-line therapies (antihistamines)

Histamine is the main mediator of urticaria, with H1-receptor activation causing itch, wealing and flare, while H2 activation plays a smaller role in weal formation. Thus, H1 antihistamines are the first-line treatment for all types of urticaria, although not all patients will respond and only about 40% will clear or almost clear at licensed doses. Antihistamines reduce pruritus, flatten wheals, shorten wheal duration and reduce wheal numbers, even though they may not clear urticaria completely. It is worth discussing the relative benefit with patients who feel that “they haven’t worked”. Generally H1 antihistamines are rapidly absorbed, reaching peak serum concentrations in 1–3 h.

Antihistamines should be taken on a daily basis, the frequency depending on their half-life. In other words, they should not be taken only when the patient is symptomatic. As a general rule, antihistamines are safe and have few significant adverse effects. They can be grouped into first-generation (classic) antihistamines, second-generation (non- or minimally sedating) antihistamines and their derivatives, and the H₂ antagonists.

 

Classical antihistamines

The use of classical antihistamines is limited by their side effects, including sedation, anticholinergic properties and paradoxical excitation in children. However, in combination with a daytime non-sedating antihistamine, they can be taken at night if sleep is disturbed by urticaria, but the following day they may interfere with skilled tasks (e.g. operating machinery and driving) or reduce the ability to concentrate at work or school and patients should be warned of this. Hydroxyzine is the most potent of the classical antihistamines. 25 mg of hydroxyzine is equivalent to 10 mg of cetirizine.

 

Second-generation antihistamines

 

The second generation of potent, specific, low-sedation H1 antihistamines is now the treatment of choice. They are usually well tolerated, with the majority of patients requiring only once-daily oral dosing. Their main advantage is low sedation at doses recommended by the manufacturer and minimal anticholinergic side effects, although an occasional individual may develop sedation with any of them. They are at least as effective as hydroxyzine and generally as effective as each other. There is no clear evidence that tolerance occurs after continued use. Very rarely, antihistamines appear to make urticaria worse, particularly with cetirizine. A European consensus paper has recommended increasing the daily dose of second-generation H₁ antihistamines up to fourfold for difficult urticaria. It is possible that their additional anti-allergic and anti-inflammatory properties may be clinically beneficial at these higher doses.

 

Cetirizine (adult dose 10 mg/day) is poorly metabolized in the liver and is excreted, predominantly in the urine, unchanged. It is also rapidly absorbed and may cause sedation and is best taken at night. Cetirizine reduces dermal eosinophil cell accumulation in vitro and in vivo. However, the clinical importance of this effect in the treatment of delayed pressure urticaria and urticarial vasculitis, where eosinophils may be an important component of the inflammatory cell infiltrate, is uncertain.

Fexofenadine is licensed for urticaria at 180 mg daily. It is the active metabolite of terfenadine, but does not appear to have the potential for ventricular arrhythmias of its parent drug at licensed doses and has the widest therapeutic window of the second generation antihistamines.

Loratadine (adult dose 10 mg daily) is a derivative of azatadine. Although loratadine is also metabolized in the liver by cytochrome P450 to some extent, so far no clinically proven, relevant drug interactions have been reported.

Desloratadine (an active metabolite of loratadine) and levocetirizine (the active enantiomer of cetirizine) probably offer no clinical advantage over their parent drugs at equivalent doses.

 

Low-sedation antihistamines are used to reduce urticarial activity, with minimal side effects. Individual response is variable, but adequate dose and timing in relationship to maximal urticarial activity is important. Alternative low-sedation antihistamines can be tried, and sedating ones added at night. A combination of an H1 antihistamine with an H2 antagonist may be more effective than H1 antihistamines alone in some patients. Use of ranitidine (adults 150 mg twice a day) is preferable to cimetidine, which has more antiandrogenic side effects and potential drug interactions.

Adverse effects of antihistamines

 

Sedation is the major risk of classical antihistamines and may be seen in some patients with second‐generation antihistamines, particularly at above licensed doses. Concerns about the potential cardiotoxity of antihistamines have receded since terfenadine and astemizole have been withdrawn from the market. The classical antihistamines hydroxyzine and diphenhydramine also have the ability to induce Q–T prolongation, emphasizing that higher than recommended doses of these antihistamines should be used only with caution.

Antihistamines in pregnancy

Antihistamines cross the placenta. They should be avoided in pregnancy and particularly in the first trimester if possible. If it is not possible, then chlorphenamine appears to be the least risky to use based on its long availability and safety record. Current guidelines on urticaria support the use of cetirizine and loratadine beyond the first trimester of pregnancy if the benefits of an antihistamine are considered to outweigh any risks of administration for an individual patient.

Antihistamines in childhood

The principles of prescribing of antihistamines in childhood are the same as for adults. Doses should follow the relevant manufacturer's recommendations.

 

Second-line therapies (targeted therapy)

Second-line therapies may be considered when urticaria does not respond well to antihistamines. They should usually be prescribed as additive therapies (to antihistamines) rather than as alternatives. It is unusual for children to need second-line therapies, except the occasional use of prednisolone for very severe acute exacerbations of chronic urticaria.

Oral corticosteroids are effective in severe urticaria when started at high doses, such as 0.5–1.0 mg prednisolone/kg/day. It should be considered primarily for the short-term management of “crisis” urticaria and serious angioedema of the throat as a rescue medication, when, often, a single dose or several daily doses will be sufficient to re-establish control with regular full-dose antihistamines. Although short courses are useful for acute exacerbations, prolonged use should be avoided because of the risk of side effects. Rebound is also a common problem and the long-term course of the urticaria is often not altered. Oral corticosteroids are often required for disease control in severe delayed pressure urticaria and urticarial vasculitis, but every attempt should be made to minimize the dose and duration.

Epinephrine (adrenaline) by subcutaneous or intramuscular injection is the treatment of choice for anaphylactic shock or severe anaphylactoid reactions whether due to an allergy, pseudo allergy, or physical urticaria. Epinephrine may also be necessary for angioedema of the oropharynx in severe acute allergic urticaria and idiopathic angioedema, but it is rarely required for chronic urticaria and is not effective for HAE. It acts rapidly by vasoconstriction and stabilizing mast cells through β-adrenoceptor stimulation. Directing epinephrine mist from an aerosol inhaler onto mucosal angioedema may be helpful for minor episodes, but for severe reactions, particularly of the anaphylactic type, epinephrine must be injected intramuscularly. Treatment should be repeated if there is no improvement after 10–15 min. Side effects of epinephrine includes tachycardia, anxiety and headache. It should be used with caution in patients with hypertension, ischemic heart disease, cerebrovascular disease and diabetes mellitus. Coadministration of tricyclic antidepressants (including doxepin) and β-blockers should be avoided. For reassurance, patients who are prone to severe acute allergic urticaria and idiopathic angioedema may carry at least two unexpired  self-administered epinephrine ‘pens’ and they need to be aware of side effects, drug interactions and potential rebound phenomenon.

The choice of other second-line therapies will be influenced by the clinical situation.

Perhaps the most promising new class of drugs is the leukotriene receptor antagonists, which have been shown to benefit aspirin-sensitive urticaria and may be of value in delayed pressure urticaria and autoimmune urticaria when added to antihistamines.

Thyroxine appears to reduce urticarial activity in some clinically euthyroid patients with elevated levels of antithyroid auto antibodies. Sulphasalazine and dapsone may be useful for delayed pressure urticaria, especially when oral corticosteroids are otherwise required for disease control.

 

Third-line therapies (immunomodulatory)

Some patients with severe urticaria unresponsive to antihistamines have an autoimmune etiology and they are treated with immunomodulators. 

Cyclosporine (3–4 mg/kg/day) for 1–3 months appears to clear or substantially benefit approximately two-thirds of patients with chronic autoimmune urticaria refractory to antihistamines. However, only 25% of responders remained clear or almost clear 4–5 months after discontinuing therapy, and symptomatic side effects (e.g. gastrointestinal) were common.

Other immunosuppressive therapies, including methotrexate, mycophenolate mofetil, azathioprine and cyclophosphamide, may work for some patients with severe chronic urticaria, if cyclosporine fails.

 

Fourth line treatment

Omalizumab (OM) (humanized anti-IgE monoclonal antibody) has shown very good results in H₁ antihistamine unresponsive spontaneous and inducible urticarias. The recommended dose of OM is 300mg by subcutaneous administration every 4 weeks and around 65% of patients experience a complete or almost complete response. Most patients experience flare up if administration of OM is delayed by > 30 days. Although OM has a significant effect  on urticarial symptoms, patients response patterns vary; fast responders experience a response within 2-4 weeks after initiating treatment, while some patients experience a slower response, which is seen 12-16 weeks after initiation of treatment. Therefore, it is recommended that OM treatment is continued for at least 6 months before considering other options. Relapse of urticarial symptoms is often seen 2-8 weeks after the last injection of OM; in such cases, retreatment with OM has obtained good results. The most commonly reported adverse effects with OM are headache, injection site itch and redness and nausea. No severe adverse effects or a complication to OM has been reported.

 

The updated version of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) [EAACI/GA²LEN/EDF/WAO] urticaria guideline published in early 2018 contains new aspects regarding the diagnosis and treatment of patients with chronic urticaria.

Chronic urticaria is a common disease, with a prevalence of at least 1 %. It is defined by the presence of pruritic wheals, angioedema or both for a period lasting more than six weeks.

With chronic urticaria, a distinction is made between chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CIndU). The former is characterized by spontaneous symptoms that are not associated with a specific trigger. The latter, on the other hand, requires specific triggers for the urticarial symptoms to occur, such as sunlight, pressure, friction, or exposure to heat or cold (Table). While CSU is two to three times more common than CIndU, many patients have more than one type of chronic urticaria. Chronic urticaria can have a significant impact on quality of life; it is associated with depression and anxiety disorders and interferes with the patient's performance in everyday life, at school and at the workplace. It is therefore crucial to provide chronic urticaria patients with the best treatment possible, that is, to attempt to achieve complete symptom control and taking into consideration as much as possible the safety of treatment and the quality of life of each individual patient.

In the vast majority of patients, this goal can be achieved with the treatment options and tools for measuring disease activity and control available today.

 

Classification of chronic urticaria

 

The classification of urticaria is based on its duration as acute (≤ 6 weeks) or chronic length (> 6 weeks) and as inducible (specific eliciting factor such as cold, heat or sunlight involved) or spontaneous (no specific eliciting factor involved). Spontaneous urticaria (also referred to as idiopathic urticaria) and inducible urticaria (also referred to as physical urticarial) often co-exist in patients.

Table

Chronic urticaria
Spontaneous urticaria (CSU)		Inducible urticaria (CIndU)
known cause	unknown cause	Physical urticaria Symptomatic dermographism Cold urticaria Solar urticaria Delayed pressure urticaria Vibratory angioedema Cholinergic urticaria Contact urticaria Aquagenic urticaria

 

 

Pathogenesis of urticaria and clinical presentation

The wheals and angioedema associated with chronic urticaria are caused by active and degranulating mast cells. Mast cell mediators such as histamine lead to vasodilatation and increased permeability, with subsequent edema in the upper dermis (wheals) and/or deep dermis and subcutis (angioedema). More than half of all CSU patients develop wheals and angioedema; up to one‐third of CSU patients show wheals but no angioedema; and about one in ten CSU patients solely experiences angioedema but no wheals.

Based on what we know today, cutaneous mast cell degranulation in patients with chronic urticaria involves autoimmune mechanisms.

Type I and IIb autoimmune mechanisms of mast cell activation in patients with CSU.

 

 

Two different mechanisms are thought to be involved in CSU. In type 1 autoimmune CSU, IgE auto antibodies bind to the high‐affinity (cutaneous) mast cell receptor. Degranulation and mediator release occurs after auto-allergen cross‐linking (endogenous allergens recognized and bound by IgE). Common CSU‐associated auto-allergens identified to date include thyroid peroxidase and interleukin 24.

In type IIb autoimmune CSU, mast cell degranulation and mediator release is caused by IgG auto antibodies directed against the high‐affinity IgE receptor or IgE molecule. The definitive diagnosis of type IIb autoimmune urticaria is based on a positive autologous serum test, a positive basophil histamine release test, and evidence of these auto antibodies, for example by means of ELISA. The mechanisms involved in mast cell degranulation in CIndU have been less well investigated. Here, too, it is postulated that autoimmune mechanisms are responsible for cutaneous mast cell degranulation.

The reaction of mast cells to degranulators is modulated by many different signals. The most important mast cell modulators in CSU include neuropeptides, complement factors, pathogen‐associated factors as well as foods and drugs in patients intolerant to the latter two. The presence and effects of one or more of these modulators, for example in case of mental stress or chronic infections, may explain their role in the pathogenesis and disease activity in patients with CSU. This also applies to the improvement in some patients following the avoidance of certain foods or the treatment of chronic infections.

 

Diagnostic approach to chronic spontaneous urticaria

The current version of the EAACI/GA²LEN/EDF/WAO urticaria guideline recommends the following diagnostic approach in patients with CSU: (1) Rule out differential diagnoses, (2) Rule out severe inflammatory diseases, and (3) measurement of disease activity and control.

Important differential diagnoses of CSU include auto-inflammatory syndromes such as Schnitzler syndrome and urticarial vasculitis (Figure). While these two disorders are likewise characterized by wheals, unlike CSU, these are ­mediated by interleukin 1 and not by histamine. It is therefore important to identify these differential diagnoses in order to initiate effective treatment. Besides chronic urticaria, recurrent angioedema without wheals also occurs in patients with bradykinin‐mediated forms of angioedema such as angiotensin‐converting enzyme (ACE) inhibitor‐induced angioedema and hereditary angioedema (Figure). In these cases, the swelling is caused by bradykinin and does not respond to classic drugs used for urticaria.

 

Figure

 

 

 

Diagnostic algorithm for patients with urticaria, angioedema or both. Abbr.: AAE, acquired angioedema with C1 inhibitor deficiency; ACE inhibitor, angiotensin‐converting enzyme inhibitor; AIS, auto-inflammatory syndrome; HAE, hereditary angioedema.

 

Once the diagnosis of chronic urticaria has been confirmed, it is important to determine which form or forms of chronic urticaria the patient has, whether they can deliberately trigger wheals or angioedema. While patients affected by the various forms of CIndU are able to do so, individuals with CSU are not.

The guideline recommends a two‐step approach with respect to laboratory tests for patients with CSU. In all CSU patients, initial tests should include C‐reactive protein levels and/or erythrocyte sedimentation rate as well as a differential blood count. While the goal of these tests is to rule out systemic inflammatory events, the urticaria itself may lead to elevated inflammatory markers, too. Depending on the history as well as on the duration and severity of chronic urticaria, patients should subsequently undergo further diagnostic workup for causes and associated dis­orders, including autoimmune diseases, infections and intolerances.

For patients with CSU, the guideline recommends measurement of disease activity, disease burden and disease control using standardized tools. This enables the physician to accurately assess disease severity and course, including treatment success. The current guideline endorses the urticaria activity score (UAS) and/or the angioedema activity score (AAS) to assess disease activity in CSU patients. In order to calculate the UAS, patients record and quantify their symptoms (wheals and pruritus) on a daily basis in a diary. The Angioedema Activity Score (AAS) is also a patient's self-reported evaluation of the activity of angioedema, which includes scoring of five key factors (duration, physical discomfort, impact on daily activities, impact on appearance, and overall severity) from 0 to 3 of each, respectively (thus a daily score of 0–15).

 

Urticaria Activity Score 7 scoring criteria for chronic spontaneous urticaria disease activity

 

 

Besides disease activity, it is also useful and recommended to assess quality‐of‐life impairment. In everyday clinical practice, assessment of disease activity as well as of quality‐of‐life impairment disease burden facilitates treatment decision making, especially prior to employing systemic therapies.

 

Diagnostic approach to chronic inducible urticaria

If CIndU is suspected, (1) differential diagnoses should be ruled out, (2) the diagnosis should be confirmed by provocation tests, (3) disease activity should be measured by determining the trigger threshold, and (4) disease burden and control should be measured.

Differential diagnoses are ruled out by taking a thorough medical history, and possibly by subsequent diagnostic tests (Figure). Provocation tests are conducted to confirm the diagnosis in all forms of CIndU. In this context, it should be noted that a patient may have multiple forms of CIndU and should therefore be tested accordingly as suggested by his/her history. When performing provocation tests, it should be borne in mind that these tests are affected by symptomatic therapies such as antihistamines. Treatment should therefore be interrupted at least three – ideally seven – days prior to testing. If this is not possible, the test result should be evaluated with caution. Provocation tests, just as determination of the trigger threshold, should be conducted prior to treatment initiation and during follow‐up. To improve comparability of test results, standardized provocation test procedures should be used.

 

Treatment of chronic urticaria

 

Treatment of chronic urticaria follows a standard approach with the goal of achieving complete freedom from symptoms. All patients should avoid known triggers. In particular, this includes certain medications such as non steroidal antiinflammatory drugs and relevant triggering stimuli in the case of CIndU. However, given that this approach results in freedom from symptoms in only very few cases, symptomatic treatment is recommended for nearly all patients, and should be based on the new treatment algorithm.

 

Recommended treatment algorithm for chronic urticaria. nsAH: non‐sedating antihistamine

 

Second‐generation H1 antihistamines remain the treatment of choice. Unlike first‐generation antihistamines, which should no longer be used, they have hardly any or only mild sedative effects. Initially, antihistamines shall be administered at the approved dose. It is important to instruct patients that antihistamines must be taken on a daily basis and not on demand.

About 40-50% of patients with CSU will not respond to standard doses of H1-antihistamines.

If continuous treatment for 2–4 weeks does not lead to adequate control of symptoms, the guideline recommends up dosing (up to four times the standard dose). Although using a higher‐than‐approved dose constitutes off‐label treatment, it is much more effective than standard‐dose therapy and has a similar side effect profile.

The guideline states that the majority of patients with urticaria not responding to standard doses will benefit from up-dosing of the second-generation H1-antihistamine and highlights studies that have documented the benefit of using up to fourfold higher than licensed doses of cetirizine, desloratadine, fexofenadine, levocetirizine, bilastine, ebastine, and rupatadine.

In contrast to the previous guidelines, and because of insufficient evidence in the literature, this recent guideline does not recommend adding another second-generation H1-antihistamine, a H2-antagonist, a leukotriene receptor antagonist or a first-generation H1-antihistamine at bedtime as next steps in treatment of antihistamine resistant cases of chronic urticaria.

Although many patients respond to up-dosing with second-generation H1-antihistamines, around half of chronic urticaria patients will not achieve satisfactory control with antihistamine treatment - even at four times the standard dose. For such patients, the guideline recommends adding omalizumab to the second-generation H1-antihistamine.

 

If sufficient improvement does not occur after 2–4 weeks of second‐generation antihistamine therapy at a higher‐than‐standard dose, omalizumab should be added to the regimen. A recombinant humanized anti‐IgE antibody, omalizumab is administered by subcutaneous injection at the recommended dose of 300 mg every four weeks. It is approved for the treatment of chronic spontaneous urticaria in patients 12 years and older. Most patients show a – usually complete – response even before the second dose. A small percentage of patients require multiple doses to achieve treatment success. Omalizumab has also been shown to be effective and safe in the treatment of CIndU patients. It is particularly effective in the treatment of cholinergic urticaria, cold urticaria, solar urticaria, heat urticaria, symptomatic dermographism, and delayed pressure urticaria but it is not FDA approved for treatment of any inducible urticaria. In CSU, omalizumab has been shown to prevent angioedema development, improve quality of life, be suitable for long-term treatment and effectively treat relapse after discontinuation. Dosing of omalizumab in CU is independent of total serum IgE.

If there is no success after six months of omalizumab therapy, off‐label treatment with cyclosporine is recommended.

The use of systemic corticosteroids in the treatment of chronic urticaria is generally to be avoided. Long term use of systemic steroids is definitely not recommended because of the myriad of associated side effects, but the 2017 guideline suggests that a short course of oral corticosteroids - up to 10 days — may be helpful in reducing disease duration/activity in acute urticaria or exacerbations of CSU.

 

Comparison among pharmacotherapies in refractory chronic urticaria patients who are resistant to high dose or combination antihistamine therapy

Patients with comorbidities