**3. Systemic urticarial syndromes**

In addition to skin disorders, many systemic diseases can cause urticarial lesions. The differen‐ tial diagnosis with ordinary urticaria should consider that systemic urticarial syndromes may cause elementary skin lesions such as papules, vesicles, hemorrhages, necrosis, and crusts in addition to urticarial skin lesions and also many systemic symptoms such as fever, asthenia, and arthralgia. Lesions usually last longer than 24–36 h, show bilateral and symmetrical distribution, and recover with hyperpigmentation and bruising [46, 47]. Systemic diseases causing urticarial skin lesions will be reviewed in this section.

#### **3.1. Vasculitides**

#### *3.1.1. Urticarial vasculitis*

Urticarial vasculitis (UV) is a separate clinicopathologic entity characterized by recurrent urticarial episodes, histopathologically showing leukocytoclastic vasculitis characteristics [48]. It is the most common clinical picture causing systemic urticarial syndrome. UV has been reported in 2–20% of the patients diagnosed with chronic urticaria [49]. It causes painful and burning skin lesions rather than itching. Urticarial lesions continue longer than 24–36 h. Central clearing of lesions is seen in time and they are accompanied by palpable purpura. Necrosis and ulceration are less common skin findings [50]. The lesions regress with a residual hyperpigmentation [47, 51]. Histopathology is essential in the diagnosis. The correct choice of the lesion is important in order to reveal true vasculitic changes. Leukocytoclastic vasculitis of the small dermal vessels characterized by a neutrophilic perivascular infiltrate, the typical findings for UV, is observed in fully developed lesions. Additionally, neutrophil fragmenta‐ tion, nuclear dust, erythrocyte extravasation, and fibrin deposition in and around the vessels are observed [50, 52].

Urticarial vasculitis is mostly idiopathic. However, an association with various drugs, sun, cold, connective tissue diseases, infections, and various malignancies (paraneoplastic) has been identified [50, 51, 53]. Among connective tissue diseases, it is most commonly seen with systemic lupus erythematosus (SLE) [53]. The most common laboratory findings in idiopathic UV are elevation of the erythrocyte sedimentation rate and reduction of serum complement levels [48]. UV is divided into two groups as mainly normocomplementemic UV (NUV) and hypocomplementemic UV (HUV), based on complement levels [51, 54]. Systemic involvement is usually absent or minimal and the prognosis is better in NUV patients. However, there is a propensity to more severe multi‐organ involvement in HUV patients [48]. The most common systemic manifestations are in the joints, kidneys, and lungs [52, 54]. Gastrointestinal and neurologic involvement can also be seen [50, 52]. Antinuclear antibody (ANA) positivity has also been reported in up to 78% of HUV patients [52, 54].

Several agents are used for UV treatment and the treatment response is variable. Systemic corticosteroids are the basis of the treatment in UV where antihistamines are usually not suf‐ ficient. UV can be controlled with prednisone at a dose of 1 mg/kg/day but can recur after the dose is decreased. Steroid‐sparing agents are used in the treatment to avoid the side effects of long‐term corticosteroids. Dapsone, colchicine, hydroxychloroquine, mycophenolate mofetil, interferon‐alpha, cyclosporine A, azathioprine, cyclophosphamide, rituximab, intravenous immunoglobulins, anakinra, and plasmapheresis are treatment agents that can be used alone or in combination with corticosteroids [50–52].

#### *3.1.2. Other vasculitides*

Urticarial lesions can be seen in the Churg‐Strauss syndrome, Wegener granulomatosis, and polyarteritis nodosa, which are characterized by vasculitis.

The Churg‐Strauss syndrome is a rare allergic granulomatous polyangiitis that usually affects middle‐aged men. The most common sign is asthma. However, hay fever, rash, gastrointes‐ tinal bleeding, and pain can also be seen. Urticarial lesions have been identified in less than 10% of the patients [55].

Polyarteritis nodosa (PAN) is a vasculitis affecting medium‐sized vessels and is very rare. Although it can affect any tissue in the body, it most commonly affects the muscles, joints, intestines, nerves, and skin. Urticarial lesions have been identified in about 6% of PAN patients [56].

#### **3.2. Immunologic disorders**

Many immunologic disorders can cause urticarial lesions. Connective tissue diseases and mainly SLE, Sjogren syndrome, dermatomyositis, and mixed connective tissue disease are important among these. It is important to know that urticarial lesions can also be seen in addi‐ tion to the existing lesions in connective tissue diseases. Although rare, urticarial lesions can also be present in juvenile rheumatoid arthritis [51].

#### **3.3. Hematologic diseases**

hyperpigmentation [47, 51]. Histopathology is essential in the diagnosis. The correct choice of the lesion is important in order to reveal true vasculitic changes. Leukocytoclastic vasculitis of the small dermal vessels characterized by a neutrophilic perivascular infiltrate, the typical findings for UV, is observed in fully developed lesions. Additionally, neutrophil fragmenta‐ tion, nuclear dust, erythrocyte extravasation, and fibrin deposition in and around the vessels

Urticarial vasculitis is mostly idiopathic. However, an association with various drugs, sun, cold, connective tissue diseases, infections, and various malignancies (paraneoplastic) has been identified [50, 51, 53]. Among connective tissue diseases, it is most commonly seen with systemic lupus erythematosus (SLE) [53]. The most common laboratory findings in idiopathic UV are elevation of the erythrocyte sedimentation rate and reduction of serum complement levels [48]. UV is divided into two groups as mainly normocomplementemic UV (NUV) and hypocomplementemic UV (HUV), based on complement levels [51, 54]. Systemic involvement is usually absent or minimal and the prognosis is better in NUV patients. However, there is a propensity to more severe multi‐organ involvement in HUV patients [48]. The most common systemic manifestations are in the joints, kidneys, and lungs [52, 54]. Gastrointestinal and neurologic involvement can also be seen [50, 52]. Antinuclear antibody (ANA) positivity has

Several agents are used for UV treatment and the treatment response is variable. Systemic corticosteroids are the basis of the treatment in UV where antihistamines are usually not suf‐ ficient. UV can be controlled with prednisone at a dose of 1 mg/kg/day but can recur after the dose is decreased. Steroid‐sparing agents are used in the treatment to avoid the side effects of long‐term corticosteroids. Dapsone, colchicine, hydroxychloroquine, mycophenolate mofetil, interferon‐alpha, cyclosporine A, azathioprine, cyclophosphamide, rituximab, intravenous immunoglobulins, anakinra, and plasmapheresis are treatment agents that can be used alone

Urticarial lesions can be seen in the Churg‐Strauss syndrome, Wegener granulomatosis, and

The Churg‐Strauss syndrome is a rare allergic granulomatous polyangiitis that usually affects middle‐aged men. The most common sign is asthma. However, hay fever, rash, gastrointes‐ tinal bleeding, and pain can also be seen. Urticarial lesions have been identified in less than

Polyarteritis nodosa (PAN) is a vasculitis affecting medium‐sized vessels and is very rare. Although it can affect any tissue in the body, it most commonly affects the muscles, joints, intestines, nerves, and skin. Urticarial lesions have been identified in about 6% of PAN

Many immunologic disorders can cause urticarial lesions. Connective tissue diseases and mainly SLE, Sjogren syndrome, dermatomyositis, and mixed connective tissue disease are

also been reported in up to 78% of HUV patients [52, 54].

polyarteritis nodosa, which are characterized by vasculitis.

or in combination with corticosteroids [50–52].

*3.1.2. Other vasculitides*

10% of the patients [55].

**3.2. Immunologic disorders**

patients [56].

are observed [50, 52].

124 A Comprehensive Review of Urticaria and Angioedema

A wide variety of hematologic diseases can cause urticarial lesions.

#### *3.3.1. Schnitzler syndrome*

Schnitzler syndrome is characterized by an urticarial rash and monoclonal gammopathy clinically and neutrophil‐mediated inflammation histologically [57]. An urticarial rash and usually IgM but rarely IgG monoclonal gammopathy are present with a chronic pattern in all the patients. Recurrent fever, bone or joint pain, increased bone density, hepato‐ or sple‐ nomegaly, lymphadenopathy, and elevated acute‐phase reactants are also accepted as minor criteria [58]. Approximately, 300 cases have been identified in the literature [57]. Risk of devel‐ oping a lymphoproliferative disorder at an approximate rate of 15% has been reported in the 10‐year follow‐up, although the syndrome usually has a benign course. The most commonly developing lymphoproliferative disease is Waldenstrom macroglobulinemia. Treatment is usually unsatisfactory, but high doses of corticosteroids, systemic antihistamines, oral cyclo‐ sporine, intravenous pulse cyclophosphamide, and pefloxacin mesylate are the therapeutic agents used [58].

#### *3.3.2. Waldenstrom macroglobulinemia*

Waldenstrom macroglobulinemia is a chronic indolent lymphoproliferative disorder [59]. Increased levels of IgM paraprotein in the circulation and infiltration of the bone marrow with lymphocytes and plasma cells are seen. Urticarial lesions can be seen in addition to purpura, edema, and ulceration [60].

#### *3.3.3. Hypereosinophilic syndromes*

This is a group of myeloproliferative disorders characterized by multiple organ damage caused by persistent eosinophilia. It is more common in young and middle‐aged patients but can be seen at any ages. Their classification is complicated. Three factors are mainly included in the diagnostic criteria. These are eosinophilia longer than 6 months (>1500/μl), no iden‐ tifiable etiology for eosinophilia, and signs and symptoms of organ involvement. The most commonly involved organs are the skin, heart, lungs, and the central and peripheral nervous systems. Skin findings are usually common and are in the form of eczematous, urticarial, and angioedema‐like findings [61, 62].

#### **3.4. Autoinflammatory syndromes**

Autoinflammatory syndromes are a group of heterogeneous single‐gene disorders causing recurrent febrile episodes and inflammatory cutaneous, mucosal, serosal, and osteoarticular manifestations [63, 64]. No infectious, autoimmune, or neoplastic reason has been shown. Excessive activation of the interleukin 1 beta (IL‐1β) pathway is most commonly held responsible in the etiopathogenesis [64].

Many syndromes such as familial Mediterranean fever (FMF), Tumor necrosis factor (TNF) receptor‐associated periodic syndrome, hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), and cryopyrin‐associated periodic syndromes have been identified among the autoinflammatory syndromes. A monogenic defect has been found but only in some of these disorders. However, all have been included within the autoinflammatory syndromes as they show similar inflammatory features [63].

Autoinflammatory syndromes mostly start in infancy or during childhood. Although most cases are familial, some are sporadic. Recurrent episodes of inflammation with fever, eleva‐ tion in acute‐phase reactants, and skin rash can be seen in the absence of an infectious or auto‐ immune etiology. Although joint and skin involvement can be seen in various forms, fever is almost always present. These symptoms can also be accompanied by systemic findings such as abdominal pain, myalgia, ocular involvement, serositis, amyloidosis, and neurological signs [63, 65].

The skin signs show variety. Urticarial lesions are the predominant skin signs, especially in cryopyrinopathies, and occur in the first year of life. They are more commonly seen as erysipelas‐like plaques in the lower extremities in FMF. Erythematous macules and urticarial lesions are seen in HIDS [51, 65].

Autoinflammatory disorders can pose a significant challenge for primary care physicians, pediatricians, dermatologists, rheumatologists, and infectious disease specialists in terms of wide‐ranging clinical spectrum. A perivascular and interstitial neutrophil‐rich infiltration suggesting neutrophilic urticarial dermatoses is observed in the histopathologic evaluation of skin lesions. Leukocytoclastic vasculitis‐like signs can also be seen [65, 66]. However, these signs are not specific. The diagnosis of autoinflammatory disorders is usually made with the clinical features and then supported by either genetic testing or the patient's response to IL‐1 inhibition or other specific therapies [63].
