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116 A Comprehensive Review of Urticaria and Angioedema

doi:10.1080/14712598.2017.1285903

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10.1126/scitranslmed.3008961

10.1111/cea.12400

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2007;**28**:313–319

1492-6-32

Hilal Gokalp and Isil Bulur

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/67993

#### **Abstract**

Urticaria is a common dermatological condition that can occur in acute and chronic forms. Common urticaria is generally easy to diagnose; however, urticarial syndromes should be considered in cases where lesions persist for greater than 24–36 h, the location of lesions has bilateral symmetry, urticarial lesions are accompanied by additional elementary lesions, and/or the patient presents with additional systemic symptoms. Additionally, urticarial syn‐ dromes should be considered for patients with typical urticarial lesions that do not respond to systemic antihistamine treatment. Hyperpigmentation or bruising can be observed fol‐ lowing resolution of urticarial syndromes. Many cutaneous and systemic diseases can cause urticarial syndromes. Systemic causes of urticarial syndromes can affect multiple organ systems and may be accompanied by systemic symptoms such as fever, asthenia, and arthralgia. Clinicopathologic correlation is essential for the accurate diagnosis of urticarial syndromes. In this chapter, cutaneous and systemic etiologies of urticarial syndromes are reviewed.

**Keywords:** urticaria, common urticaria, urticarial syndromes, cutaneous urticarial syndromes, systemic urticarial syndromes

#### **1. Introduction**

Urticaria is a disease with a lifetime prevalence of 25–30% and is characterized by itchy urticarial lesions and/or angioedema [1, 2]. Although its physiopathology is not well under‐ stood, cutaneous mast cells are the main causative factor that is responsible for the release of histamine and other mediators [3, 4]. The disease is divided into acute and chronic depending on whether the duration is less or more than 6 weeks. While acute urticaria is often limited and the cause can be determined in most patients, chronic urticaria is a long‐term disease, and further investigation is required in terms of accompanying disorders or autoimmunity [5]. The diagnosis of common urticaria is usually made easily. However, some difficulties in terms

© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

of response to treatment, accompanying lesions, and systemic findings can be seen in some patients. Various disorders, both cutaneous and systemic, are included in the spectrum called urticarial syndrome (**Table 1**). In general, lesions lasting longer than 24–36 h, showing bilat‐ eral symmetric involvement, with elementary lesions other than urticaria and accompanying systemic symptoms should bring urticarial syndromes to mind. Clinicopathologic correlation is essential in the diagnosis of urticarial syndromes [1, 5]. Cutaneous and systemic disorders that may cause the urticarial syndrome will be reviewed in this section.


**Table 1.** Cutaneous and systemic urticarial syndromes.

#### **2. Cutaneous urticarial syndromes**

Various skin disorders can cause urticarial lesions and can be confused with common urticaria.

#### **2.1. Urticarial dermatitis**

Urticarial dermatitis is a clinical picture where urticarial plaques and edematous lesions are combined and is usually seen in the elderly. Urticarial dermatitis is quite itchy and often characterized by diffuse and symmetrical involvement of the body and proximal extremities. Facial and palmoplantar region involvement is usually not present. Existing lesions may persist for days or even weeks. Excoriations and lichenification due to the severe itching may be observed in time. It usually has a chronic relapsing course and spontaneous regression is very rare [5, 6]. Most pathologists describe urticarial dermatitis as a "dermal hypersensitivity reaction." Papillary dermal edema and minimal epidermal spongiosis with superficial peri‐ vascular lymphocytic and eosinophilic infiltration are seen on histopathologic examination [6, 7]. While the etiologic agents most commonly held responsible are drugs, detecting the triggering agent can sometimes be difficult [6]. Low to moderate doses of systemic steroids can provide relief in patients' resistant to topical steroids and systemic antihistamines [5, 8].

#### **2.2. Contact dermatitis**

of response to treatment, accompanying lesions, and systemic findings can be seen in some patients. Various disorders, both cutaneous and systemic, are included in the spectrum called urticarial syndrome (**Table 1**). In general, lesions lasting longer than 24–36 h, showing bilat‐ eral symmetric involvement, with elementary lesions other than urticaria and accompanying systemic symptoms should bring urticarial syndromes to mind. Clinicopathologic correlation is essential in the diagnosis of urticarial syndromes [1, 5]. Cutaneous and systemic disorders

> • Urticarial vasculitis • Other vasculitides

• Connective tissue diseases

• Juvenile rheumatoid arthritis

• Waldenstrom macroglobulinemia

• Hypereosinophilic syndromes

• Non‐Hodgkin lymphoma (B cell)

• Hereditary periodic fever syndromes • Cryopyrin‐associated periodic syndromes • Other autoinflammatory syndromes

Autoinflammatory syndromes

Hematologic diseases

• Schnitzler syndrome

• Polycythemia vera

• SLE, Sjogren syndrome, dermatomyositis

Various skin disorders can cause urticarial lesions and can be confused with common urticaria.

Urticarial dermatitis is a clinical picture where urticarial plaques and edematous lesions are combined and is usually seen in the elderly. Urticarial dermatitis is quite itchy and often

that may cause the urticarial syndrome will be reviewed in this section.

**Cutaneous urticarial syndromes Systemic urticarial syndromes**

Mastocytosis Immunologic disorders

Urticarial dermatitis Vasculitides

118 A Comprehensive Review of Urticaria and Angioedema

Contact dermatitis Papular urticaria

Exanthematous drug eruption Autoimmune bullous disorders

• Bullous pemphigoid • Gestational pemphigoid • Linear IgA dermatosis • Dermatitis herpetiformis • Epidermolysis bullosa acquisita

• Wells syndrome

**2. Cutaneous urticarial syndromes**

**Table 1.** Cutaneous and systemic urticarial syndromes.

Pruritic urticarial papules and plaques of pregnancy

• Autoimmune progesterone/estrogen dermatitis

Rare cutaneous urticarial syndromes

• Interstitial granulomatous dermatitis • Neutrophilic eccrine hidradenitis • Urticaria‐like follicular mucinosis

**2.1. Urticarial dermatitis**

Contact dermatitis (CD) develops after contact with allergic and/or irritant agents and is fairly common. The sensitizers that most commonly cause allergic CD are poison ivy, nickel, form‐ aldehyde, and fragrances that are included in many cosmetics. Irritant CD is also called non‐ immunologic contact dermatitis and is most commonly due to fragrances, flavoring agents, and preservatives [9–11]. While CD usually causes itchy eczematous lesions, urticarial lesions may rarely be seen due to dermal edema. The border between CD and contact urticaria is not clear. Dermal edema is seen more commonly in contact urticaria, and this is accepted as the most important difference with CD. Histopathologic investigation is usually not required in CU as it develops in the region that contacts the allergic and/or irritant agent. However, if performed, a spongiotic dermatitis picture characterized by a mixed inflammatory infiltrate formed of lymphocytes, histiocytes, and eosinophils is often observed in CD. Only dermal changes are seen in CU and epidermal spongiosis is not seen [12, 13]. A patch test and/or specific IgE investigation is recommended to detect the agent causing the problem.

#### **2.3. Papular urticaria**

Papular urticaria is a kind of allergic hypersensitivity reaction developing after arthropod bites. It is most common in children at the age of 2–10 years [14]. It usually develops in open regions of the body such as the arms, lower leg, and face due to insect bites from fleas, mos‐ quitoes, or bedbugs especially in the summer [15]. The genital, perianal, and axillary regions are generally protected. Vesicles, excoriation, and post‐inflammatory hyperpigmentation can be gradually observed in the middle of the lesion that starts as an itchy papule. Mostly, acute‐ type localized insect bites have urticarial features [16]. Diagnosis is usually clinical but can rarely be confused with other disease such as varicella, miliaria rubra, and Gianotti‐Crosti syndrome [17]. Nonsedating antihistamines and moderate‐potency topical corticosteroids for itching are usually adequate for treatment [14].

#### **2.4. Exanthematous drug eruptions**

Exanthematous drug eruptions, also called morbilliform or maculopapular drug eruptions, are the most common drug hypersensitivity reaction [18]. They are present in form of erythematous fixed macules, papules, or wheal‐like lesions with a bilateral and symmetrical distribution especially on the body after an average of 1 week following drug administration. The lesions become confluent in time and improve by leaving transient hyperpigmentation while regressing [5]. The mucous membranes are usually not involved. However, the mucous membranes (oral, conjunctival, nasal, or anogenital) and skin appendages (hair and nails) may be involved in patients with severe drug eruption. Mild fever can be seen. The medica‐ tion history is essential in the diagnosis. Histopathologic diagnosis is not always required. Biopsy sometimes does not help in the diagnosis because it does not contain specific signs. Skin biopsy is generally recommended in the case of drug use that may cause a drug erup‐ tion, fever >38°C, and the presence of erythroderma, blisters, and purpura or pustules and mucous membrane involvement [19]. Discontinuing the suspected drug immediately is recommended in the treatment. Topical corticosteroids and systemic antihistamines are rec‐ ommended for symptomatic treatment. However, short‐term moderate‐high dose (predni‐ sone 1–2 mg/kg/day) systemic corticosteroid treatment can be recommended in those with a severe exanthematous drug reaction [20].

#### **2.5. Cutaneous mastocytosis (Urticaria pigmentosa)**

Mastocytosis is a group of disorders characterized by the accumulation of mast cells in one or more organs. It is divided into two main groups as cutaneous and systemic [21]. Urticaria pigmentosa (UP) is the most common type of cutaneous mastocytosis both in childhood and adulthood. It presents with brown macules and papules, especially in the trunk or limbs. However, it can be seen as an urticarial rash that can affect the entire body in children. Dermographism‐urticaria (Darier finding) development after skin rubbing is present in most cases [21, 22]. Healing is usually with post‐inflammatory hyperpigmentation. The number of lesions is variable. The most common symptoms are itching and flushing. However, bulla development, recurrent syncope, and even anaphylaxis can be seen. Regression in symp‐ toms is seen in the majority of the patients until adolescence with full improvement in 50% [23]. Although clinicopathologic correlation is recommended for the diagnosis, histopatho‐ logic characteristics may not always be obvious. The treatment is usually symptomatic in children. Phototherapy is the primary treatment in widespread maculopapular lesions seen in adults [24].

#### **2.6. Autoimmune bullous disorders**

Bullous pemphigoid, gestational pemphigoid, linear IgA dermatosis, and epidermolysis bullosa acquisita are disorders due to autoantibodies toward various basal membrane components and characterized by subepidermal bulla formation related to these antigens. Another common characteristic of these disorders is the possibility of urticarial lesions.

#### *2.6.1. Bullous pemphigoid*

Bullous pemphigoid (BP) is an autoimmune bullous disorder that is especially observed in elderly people and often accompanied by severe itching. It presents with tense bullae follow‐ ing a prodromal stage lasting weeks or even months. Bulla development may not be observed in some patients. Pruritic eczematous and papular or urticaria‐like skin lesions are commonly observed in the prodromal period [25–27]. They may develop on a non‐inflammatory base or an urticarial‐erythematous base [28]. The body, extremity flexures, and axillary and inguinal folds are the main regions involved. Bilateral symmetrical involvement is usually present [25, 26, 28]. BP may not be considered in patients with a long‐term prodromal period. The gold standard in the diagnosis is histopathology and direct immunofluorescence. Detection of autoantibodies in the serum with indirect immunofluorescence has become the standard for the diagnosis at many centers [29].

#### *2.6.2. Gestational pemphigoid*

distribution especially on the body after an average of 1 week following drug administration. The lesions become confluent in time and improve by leaving transient hyperpigmentation while regressing [5]. The mucous membranes are usually not involved. However, the mucous membranes (oral, conjunctival, nasal, or anogenital) and skin appendages (hair and nails) may be involved in patients with severe drug eruption. Mild fever can be seen. The medica‐ tion history is essential in the diagnosis. Histopathologic diagnosis is not always required. Biopsy sometimes does not help in the diagnosis because it does not contain specific signs. Skin biopsy is generally recommended in the case of drug use that may cause a drug erup‐ tion, fever >38°C, and the presence of erythroderma, blisters, and purpura or pustules and mucous membrane involvement [19]. Discontinuing the suspected drug immediately is recommended in the treatment. Topical corticosteroids and systemic antihistamines are rec‐ ommended for symptomatic treatment. However, short‐term moderate‐high dose (predni‐ sone 1–2 mg/kg/day) systemic corticosteroid treatment can be recommended in those with a

Mastocytosis is a group of disorders characterized by the accumulation of mast cells in one or more organs. It is divided into two main groups as cutaneous and systemic [21]. Urticaria pigmentosa (UP) is the most common type of cutaneous mastocytosis both in childhood and adulthood. It presents with brown macules and papules, especially in the trunk or limbs. However, it can be seen as an urticarial rash that can affect the entire body in children. Dermographism‐urticaria (Darier finding) development after skin rubbing is present in most cases [21, 22]. Healing is usually with post‐inflammatory hyperpigmentation. The number of lesions is variable. The most common symptoms are itching and flushing. However, bulla development, recurrent syncope, and even anaphylaxis can be seen. Regression in symp‐ toms is seen in the majority of the patients until adolescence with full improvement in 50% [23]. Although clinicopathologic correlation is recommended for the diagnosis, histopatho‐ logic characteristics may not always be obvious. The treatment is usually symptomatic in children. Phototherapy is the primary treatment in widespread maculopapular lesions seen

Bullous pemphigoid, gestational pemphigoid, linear IgA dermatosis, and epidermolysis bullosa acquisita are disorders due to autoantibodies toward various basal membrane components and characterized by subepidermal bulla formation related to these antigens. Another common

Bullous pemphigoid (BP) is an autoimmune bullous disorder that is especially observed in elderly people and often accompanied by severe itching. It presents with tense bullae follow‐ ing a prodromal stage lasting weeks or even months. Bulla development may not be observed

characteristic of these disorders is the possibility of urticarial lesions.

severe exanthematous drug reaction [20].

120 A Comprehensive Review of Urticaria and Angioedema

in adults [24].

*2.6.1. Bullous pemphigoid*

**2.6. Autoimmune bullous disorders**

**2.5. Cutaneous mastocytosis (Urticaria pigmentosa)**

Gestational pemphigoid is a rare autoimmune skin disorder seen during pregnancy. It is characterized by a severe itchy and bullous eruption due to damage in the basement membrane of the skin by autoantibodies developing against placental BP180 (BPAG2/ collagen XVII) [30]. However, urticarial and eczematous lesions may be seen before and/or during bulla development in some cases. The onset is usually with severe itching around the belly. Red papules, urticarial plaques, or erythema multiforme‐like targetoid lesions develop. However, cases where the urticarial or targetoid lesions lasted longer have also been reported. Histopathology, direct immunofluorescence, and indirect immunofluorescence are important in the diagnosis [5, 29, 31].

#### *2.6.3. Linear IgA bullous dermatosis*

Linear IgA bullous dermatosis (LABD) is a mucocutaneous autoimmune subepidermal vesic‐ ulobullous disorder. Although the etiopathogenesis is not fully known, it is thought to be associated with drugs, infections, autoimmune diseases, gastrointestinal diseases, and malig‐ nancies [32, 33]. There can be clear or hemorrhagic lesions, tense vesicles, or bullae appearing on an erythematous or urticarial base [34]. When erythematous or urticarial lesions last a long time, the diagnosis of bullous disorders can be missed. The diagnosis is made with clinical, histopathologic, and immunologic data as in other autoimmune disorders.

#### *2.6.4. Epidermolysis bullosa acquisita*

Epidermolysis bullosa acquisita (EBA) is a rare acquired, chronic subepidermal bullous dis‐ ease of the skin and mucous membranes. It is characterized by antibodies developing against type VII collagen, which is the major component of anchoring fibrils. Clinical presentation is usually in the form of non‐inflammatory bullous lesions that improve with scarring and milia formation in trauma‐prone acral regions. However, in addition to the classic presentation, BP‐like presentation, cicatricial pemphigoid‐like presentation, Brunsting‐Perry pemphigoid presentation, and LABD‐like disease can also be seen. Urticarial lesions can be observed with various durations, especially with a BP‐like and LABD‐like presentation. Clinical, histopatho‐ logic, and immunologic investigations are required in the diagnosis. Colchicine, dapsone, plasmapheresis, photopheresis, infliximab, and intravenous immunoglobulin are the most commonly used treatment agents. However, treatment satisfaction is usually low [5, 35].

#### **2.7. Pruritic urticarial papules and plaques of pregnancy**

Pruritic urticarial papules and plaques of pregnancy (PUPPP) is the itchiest dermatosis of pregnancy. PUPPP is seen in the form of erythematous, urticarial plaques, and papules and usually starts from the abdomen and extends to the thighs, legs, back, buttocks, arms, and breasts. However, the periumbilical region is protected. The lesions usually regress within 6 weeks in the postpartum period [36, 37]. In addition to erythematous and urticarial plaques, targetoid and vesicular lesions can be seen in approximately half of the patients as the disease progresses. Moisturizers, topical corticosteroids, and antihistamines can be recommended for symptomatic relief in patients with severe itching [36].

#### **2.8. Rare cutaneous urticarial syndromes**

Autoimmune progesterone/estrogen dermatitis, interstitial granulomatous dermatitis, eosin‐ ophilic cellulitis (Wells syndrome), neutrophilic eccrine hidradenitis (NEH), and urticaria‐like follicular mucinosis are rare cutaneous urticarial syndromes.

#### *2.8.1. Autoimmune progesterone/estrogen dermatitis*

Autoimmune progesterone dermatitis (APD) is a rare dermatosis that causes inflammation at the luteal phase of the menstrual cycle and presents with several skin findings. Skin signs include urticarial, eczematous and vesiculopustular eruption, targetoid lesions, and angioedema [38, 39]. Urticaria is seen in about half of patients [5]. There is no specific diagnostic test. A history of premenstrual exacerbation, prevention of lesions with ovulation inhibition, and a positive reaction to intradermal progesterone injection are helpful in the diagnosis [39]. Autoimmune estrogen dermatitis has also been identified in the literature but only in low numbers [5].

#### *2.8.2. Interstitial granulomatous dermatitis*

Interstitial granulomatous dermatitis (IGD) is a rare dermatosis and accepted as a separate histopathologic entity [40]. Papules, nodules, plaques, and an urticarial rash can be observed in the disorder that is more common in women and the elderly people. Of the cases identified until today, two‐thirds have had a chronic course and the remaining a recurrent and episodic course. Recognizing IGD is quite important in order to indicate the underlying autoimmune disorders [5, 40]. Clinicopathological correlation is essential for the diagnosis.

#### *2.8.3. Wells syndrome (eosinophilic cellulitis)*

Wells syndrome is a rare dermatosis that presents as acute, recurrent, itchy, erythematous, and edematous lesions [41]. Although it brings bacterial cellulitis to mind first in the clinic, not responding to systemic antibiotics is an important indicator in the diagnosis. Another differential diagnosis is urticaria due to the presence of urticarial lesions. In addition to bacterial cellulitis and urticaria, it can be confused with insect bite, contact dermatitis, angioedema, and hypereosinophilic syndrome [42]. Clinicopathologic correlation is important in the diagnosis. Dermal edema, eosinophilic dermal infiltration, and free eosinophilic granules coating collagen bundles ("flame figures") are observed histopathologically. However, the histopathologic signs change in time. Peripheral eosinophilia may also be present in the acute phase [41, 42].

#### *2.8.4. Neutrophilic eccrine hidradenitis*

**2.7. Pruritic urticarial papules and plaques of pregnancy**

symptomatic relief in patients with severe itching [36].

follicular mucinosis are rare cutaneous urticarial syndromes.

**2.8. Rare cutaneous urticarial syndromes**

122 A Comprehensive Review of Urticaria and Angioedema

*2.8.1. Autoimmune progesterone/estrogen dermatitis*

only in low numbers [5].

*2.8.2. Interstitial granulomatous dermatitis*

*2.8.3. Wells syndrome (eosinophilic cellulitis)*

Pruritic urticarial papules and plaques of pregnancy (PUPPP) is the itchiest dermatosis of pregnancy. PUPPP is seen in the form of erythematous, urticarial plaques, and papules and usually starts from the abdomen and extends to the thighs, legs, back, buttocks, arms, and breasts. However, the periumbilical region is protected. The lesions usually regress within 6 weeks in the postpartum period [36, 37]. In addition to erythematous and urticarial plaques, targetoid and vesicular lesions can be seen in approximately half of the patients as the disease progresses. Moisturizers, topical corticosteroids, and antihistamines can be recommended for

Autoimmune progesterone/estrogen dermatitis, interstitial granulomatous dermatitis, eosin‐ ophilic cellulitis (Wells syndrome), neutrophilic eccrine hidradenitis (NEH), and urticaria‐like

Autoimmune progesterone dermatitis (APD) is a rare dermatosis that causes inflammation at the luteal phase of the menstrual cycle and presents with several skin findings. Skin signs include urticarial, eczematous and vesiculopustular eruption, targetoid lesions, and angioedema [38, 39]. Urticaria is seen in about half of patients [5]. There is no specific diagnostic test. A history of premenstrual exacerbation, prevention of lesions with ovulation inhibition, and a positive reaction to intradermal progesterone injection are helpful in the diagnosis [39]. Autoimmune estrogen dermatitis has also been identified in the literature but

Interstitial granulomatous dermatitis (IGD) is a rare dermatosis and accepted as a separate histopathologic entity [40]. Papules, nodules, plaques, and an urticarial rash can be observed in the disorder that is more common in women and the elderly people. Of the cases identified until today, two‐thirds have had a chronic course and the remaining a recurrent and episodic course. Recognizing IGD is quite important in order to indicate the underlying autoimmune

Wells syndrome is a rare dermatosis that presents as acute, recurrent, itchy, erythematous, and edematous lesions [41]. Although it brings bacterial cellulitis to mind first in the clinic, not responding to systemic antibiotics is an important indicator in the diagnosis. Another differential diagnosis is urticaria due to the presence of urticarial lesions. In addition to bacterial cellulitis and urticaria, it can be confused with insect bite, contact dermatitis, angioedema, and hypereosinophilic syndrome [42]. Clinicopathologic correlation is important in the diagnosis.

disorders [5, 40]. Clinicopathological correlation is essential for the diagnosis.

Neutrophilic eccrine hidradenitis (NEH) is a very rare dermatosis seen in patients with malig‐ nancy or those receiving chemotherapy. The majority of the cases are acute myelogenous leukemia patients receiving chemotherapy [43]. It clinically presents with fixed erythematous and edematous papules and plaques. It is usually accompanied by fever. Histopathologic signs are important in the diagnosis. It is histopathologically characterized by neutrophilic infiltration accompanied by necrosis around eccrine glands and secretory coils. No specific treatment is required as it is usually self‐limiting. However, systemic corticosteroid treatment has been reported to shorten the duration of the lesions and the fever [5, 44].

#### *2.8.5. Urticaria‐like follicular mucinosis*

Urticaria‐like follicular mucinosis (ULFM) is a very rare disease that presents with itching, urticarial papules, and plaques on an erythematous base, usually in the head and neck. It is usually seen in middle‐aged men. Spontaneous improvement is common. However, recur‐ rence can be seen. Histopathological characteristics are important in the diagnosis. Cystic spaces filled with mucin in the outer sheath of hair follicles are histologically seen [45].
