**12. Angioedema without wheals**

As described previously in this chapter, angioedema is defined as swellings of the deep dermis and subcutaneous tissue. Clinically, there is non-pitting asymmetrically distributed edema usually involving the face. Angioedema typically resolves spontaneously in less than 72 hours [41].

Clinically a variety of conditions may cause swellings that resemble angioedema. Acute contact dermatitis develops after exposure to a foreign substance. When acute contact dermatitis involves the face, it is frequently misdiagnosed as angioedema. Abrupt onset of angioedema associated with diffuse maculopapular rash, fever, eosinophilia and lymphadenopathy is seen in drug rash with eosinophilia and systemic symptoms (DRESS) Syndrome. Periorbital edema of dermatomyositis may mimic angioedema [41]. Other diseases to consider in differential diagnosis of angioedema are superior vena cava syndrome, myxedema of hypothyroidism, photodermatitis, Crohn's disease of the mouth and lips, facial cellulitis and Melkersson-Rosenthal syndrome [18, 41].

Angioedema without wheals can be classified as hereditary angioedema, acquired angioedema, drug-induced angioedema and idiopathic angioedema [42].

#### **12.1. Hereditary angioedema**

#### *12.1.1. Epidemiology*

Hereditary angioedema is rare genetic disease with a prevalence of about 1:10,000– 1:50,000. The inheritance is autosomal dominant. In 20% of cases, a positive family history of the disease cannot be obtained because these cases occur due to spontaneous mutations [42].

#### *12.1.2. Etiology and pathogenesis*

Two types of the disease have been defined, both concerning the inhibitor of the first component of human complement (C1). Type I accounts for 80–85% of cases and is characterized by low C1 inhibitor levels and function. Type II comprises the remaining 15–20% of cases and it is associated with normal levels of poorly functioning C1 inhibitor. Both types of hereditary angioedema result in low levels of C4; during acute attacks C2 levels may also decrease [42].

The recently described hereditary angioedema type III is not associated with C1 inhibitor deficiency or dysfunction. The etiology of this very rare type of hereditary angioedema is not fully understood. It mostly affects women. Estrogens and mutations in factor XII are thought be involved in pathogenesis [43, 44].

C1 inhibitor is the major regulator of complement and contact system activation. With the decreased activity of C1 inhibitor, unopposed activation of contact system leads to generation of bradykinin. Bradykinin induces relaxation in vascular smooth muscle and increases vascular permeability causing angioedema [42, 44].

Trauma, stress, infection, menstruation, oral contraceptives, hormonal replacement therapy and angiotensin-converting enzyme (ACE) inhibitors can trigger the attacks. However an underlying trigger cannot be found in most of the cases [42, 44].

#### *12.1.3. Clinical features*

**11.6. Phototherapy**

72 hours [41].

Rosenthal syndrome [18, 41].

**12.1. Hereditary angioedema**

*12.1.2. Etiology and pathogenesis*

*12.1.1. Epidemiology*

mutations [42].

**12. Angioedema without wheals**

20 A Comprehensive Review of Urticaria and Angioedema

Efficacy of phototherapy, both narrowband UVB and PUVA, has been shown in several studies. Phototherapy is not recommended in urticaria guidelines; still it appears to be a safe and

As described previously in this chapter, angioedema is defined as swellings of the deep dermis and subcutaneous tissue. Clinically, there is non-pitting asymmetrically distributed edema usually involving the face. Angioedema typically resolves spontaneously in less than

Clinically a variety of conditions may cause swellings that resemble angioedema. Acute contact dermatitis develops after exposure to a foreign substance. When acute contact dermatitis involves the face, it is frequently misdiagnosed as angioedema. Abrupt onset of angioedema associated with diffuse maculopapular rash, fever, eosinophilia and lymphadenopathy is seen in drug rash with eosinophilia and systemic symptoms (DRESS) Syndrome. Periorbital edema of dermatomyositis may mimic angioedema [41]. Other diseases to consider in differential diagnosis of angioedema are superior vena cava syndrome, myxedema of hypothyroidism, photodermatitis, Crohn's disease of the mouth and lips, facial cellulitis and Melkersson-

Angioedema without wheals can be classified as hereditary angioedema, acquired angio-

Hereditary angioedema is rare genetic disease with a prevalence of about 1:10,000– 1:50,000. The inheritance is autosomal dominant. In 20% of cases, a positive family history of the disease cannot be obtained because these cases occur due to spontaneous

Two types of the disease have been defined, both concerning the inhibitor of the first component of human complement (C1). Type I accounts for 80–85% of cases and is characterized by low C1 inhibitor levels and function. Type II comprises the remaining 15–20% of cases and it is associated with normal levels of poorly functioning C1 inhibitor. Both types of hereditary angioedema result in low levels of C4; during acute attacks C2 levels may also decrease [42].

edema, drug-induced angioedema and idiopathic angioedema [42].

effective therapeutic modality for patients with refractory chronic urticaria [38–40].

Clinically angioedema mostly involves the face, tongue and lips, abdomen, larynx, extremities and genitalia [42]. Any part of the body can be affected including chest, joints, muscles, etc. Abdominal colicky pain, nausea and vomiting are manifestations of gastrointestinal involvement. Edema of the upper airway tract can be life threatening [42, 43]. The onset of disease is usually in childhood mostly between 8 and 12 years. Episodic swellings last 1–5 days before subsiding. A serpiginous rash called erythema marginatum, fatigue and muscle aches are prodromal symptoms reported by 50% of patients with hereditary angioedema [44].

#### *12.1.4. Prophylaxis and treatment*

Management of hereditary angioedema can be classified under three different categories, which are treatment of the attacks, short-term or procedural prophylaxis and long-term prophylaxis [43].

Management of acute attacks can be accomplished by replacement of C1 inhibitor or alternatively by using icatibant or ecallantide. Plasma-derived or recombinant C1 inhibitors are available for intravenous replacement of C1 inhibitor. Icatibant is bradykinin B2 receptor antagonist. Human C1 inhibitors and icatibant are approved for self-administration. These agents are most effective when given as early as possible during the attacks. Ecallantide works by reversible inhibition of kallikrein and is approved by FDA for use in patients older than 12 years of age. Application by a healthcare professional is imperative because of a high risk of developing anaphylactic reaction [43].

As noted above trauma is among the well-known triggers of an angioedema attack. Thus a short-term prophylaxis is indicated before interventions in the upper aerodigestive tract, such as intubation, bronchoscopy or esophagogastroduodenoscopy. For this purpose C1 inhibitors are the first-choice agents. Androgens, which have been the mainstay of management of patients with hereditary angioedema in the past, are no longer considered as first-line options because of associated side effects and are only used when C1 inhibitor therapy is not available. Weight gain, hepatotoxicity, virilism and hypertension are among the various side effects of androgen therapy [43, 44].

Long-term prophylaxis can be initiated if treatment of acute attacks does not result in adequate symptom control. C1 inhibitor concentrates are recommended as first-line agents. Androgens and tranexamic acid are less favored because of high risk of adverse effects and low treatment efficacy, respectively [43].

### **12.2. Acquired angioedema**

#### *12.2.1. Etiology and pathogenesis*

Acquired angioedema is an autoimmune disease characterized by autoantibodies against C1 inhibitor [44]. A lymphoproliferative disorder such as non-Hodgin lymphoma or monoclonal gammopathy or an autoimmune disease is found in many of the cases. These associations suggest that pathological B cell clones may be responsible for acquired angioedema [45].

Acquired angioedema is divided into two types. Type I acquired angioedema is due to massive consumption of C1 inhibitor, presumably by tumor-related immune complexes. Type II acquired angioedema occurs due to the production of anti-C1 inhibitor autoantibodies [25].

#### *12.2.2. Clinical features*

Clinical features of acquired angioedema are similar to those seen in hereditary angioedema. Abdominal involvement is less frequent [44]. Absence of family history and late onset of symptoms at 4th decade are distinguishing features [42]. Laboratory evaluation of patients with acquired angioedema reveals low C4 levels and decreased C1 inhibitor activity similar to hereditary angioedema; but also decreased levels of C1q [44].

#### *12.2.3. Treatment*

Treatment of acquired angioedema mostly depends on treatment of the underlying disease [42]. Although response rates are low, treatments used for hereditary angioedema are frequently applied. Acute attacks can be managed by administration of C1 inhibitor concentrate or alternatively by using icatibant or ecallantide. High-dose corticosteroid therapy is used in order to reduce production of autoantibodies but it is frequently ineffective and has many adverse effects. Rituximab has also been shown to be effective in decreasing autoantibody production against C1 inhibitor. Although several reports of patients successfully treated with rituximab exist, the responses can be inconsistent [44, 46].

#### **12.3. Drug-induced angioedema**

Drug-induced angioedema is most typically associated with the use of angiotensin-converting enzyme (ACE) inhibitors. Angiotensin receptor blockers, nonsteroidal anti-inflammatory drugs, fibrinolytics and oral contraceptives can also induce isolated angioedema [18].

Angioedema due to angiotensin-converting enzyme inhibitors occurs in 0.1–6% of patients under treatment with ACE inhibitors. It tends to develop more commonly in women, smokers and in patients of African American descent [47]. ACE inhibitor angioedema mostly develops at the first month of treatment but may also occur years after starting the medication [42].

As the underlying mechanism involves elevated levels of bradykinin, antihistamines and corticosteroids are not helpful in the management of drug-induced angioedema. Although not FDA-approved for this indication, bradykinin receptor antagonist icatibant and kallikrein inhibitors are effective treatment agents [42, 48].

#### **12.4. Idiopathic angioedema**

The term idiopathic angioedema is used when there is no identifiable cause for the recurrent angioedema attacks without wheals. Idiopathic angioedema is a diagnosis of exclusion. C1 inhibitor deficiency, factor XII mutation, treatment with ACE inhibitors must be ruled out [49]. The condition is mostly well-controlled with prophylactic antihistamines [5].
