20 HOW TO TREAT : URTICARIA IN ADULTS
20 HOW TO TREAT : URTICARIA IN ADULTS
3 NOVEMBER 2023 ausdoc . com . au
Coelho de Sá D , et al . An Bras Dermatol 2016 / CC BY-NC 4.0 ( with permission ): bit . ly / 3XCb3ln
Figure 1 . Schnitzler syndrome .
Angioedema refers to localised non-pitting oedema of subcutaneous or submucosal tissues . It is classified by pathogenesis into histaminergic ( mast cell mediator induced ) and non-histaminergic ( bradykinin induced ). 7 Depending on the location , angioedema mimics can include facial lymphoedema , granulomatous cheilitis , the early stages of scleroderma and severe hypothyroidism , which should be classified separately .
EPIDEMIOLOGY
TABLE 1 lists the epidemiology of urticaria .
AETIOLOGY
ACUTE urticaria is a self-limiting condition ; extensive investigation to identify an underlying cause is not usually undertaken . In both children and adults , the most common cause for acute urticaria is an underlying infection . 17 , 18 In a smaller proportion of patients , the cause is immunoglobulin E ( IgE ) -mediated hypersensitivity , commonly known as an allergic reaction . In these cases , a temporal relationship between exposure to a food , medication or insect sting is usually apparent on clinical assessment .
The underlying aetiology of chronic spontaneous urticaria is the subject of ongoing study . It is thought to be a heterogeneous condition , with autoimmune and autoallergic mechanisms postulated . In some patients , chronic infections ( such as Helicobacter pylori and Strongyloides stercoralis ), autoimmune conditions ( such as rheumatoid arthritis , SLE and autoimmune thyroiditis ) and malignancy ( such as lymphoma and myeloma ) are identified . 19 Previously suspected associations of chronic urticaria with hepatitis B and C may have been overstated . 20
CIndU is caused by mast cell activation in the setting of specific
Box 2 . Differential diagnoses of urticaria
• Urticarial vasculitis .
• Hypereosinophilic syndrome .
• Schnitzler syndrome : an autoinflammatory disease characterised by chronic nonpruritic urticaria and monoclonal gammopathy ( see figure 1 ).
• Autoinflammatory urticarial syndrome .
• Cutaneous or systemic mastocytosis .
• Mast cell activation syndrome .
• Autoimmune progesterone dermatitis .
• Cryopyrin-associated periodic syndromes .
Source : Matos AL et al 2022 9
triggers , including pressure , friction , cold , heat , vibration , water and sunlight . The cholinergic subtype of CIndU is triggered by increased body temperature during exercise , emotional stress or passive exposure to heating . The underlying cause of mast cell reactivity following trigger exposure in CIndU is unknown . 10
Causes of non-histaminergic angioedema include hereditary angioedema ( HAE ), ACEI / drug-associated angioedema and acquired C1-esterase inhibitor deficiency / acquired angioedema . Histaminergic angioedema is thought to be driven by similar mechanisms as chronic spontaneous urticaria .
PATHOGENESIS
THE shared pathogenesis of all subtypes of urticaria is dermal mast cell activation and subsequent release of inflammatory mediators . Mast cells are found in the upper and lower dermis , typically close to blood vessels , and can be activated by a variety of triggers . On activation , these cells release histamine , leukotrienes , prostaglandins and cytokines that
Table 1 . The epidemiology of urticaria Acute urticaria
mediate the hallmark signs of urticaria . Histamine activates sensory nerves and dilatation of blood vessels , resulting in pruritis and erythema respectively . Leukotrienes and prostaglandins are potent vasodilators that induce plasma extravasation , producing localised
20 , 21 oedema .
Two endotypes of chronic spontaneous urticaria , with differing mechanisms , are recognised . The first — termed autoallergic or type I autoimmune chronic spontaneous urticaria — is sensitisation with IgE autoantibodies targeting native host antigens , such as thyroid peroxidase , tissue factor , interleukin-24 and double-stranded DNA . 22
The second — type IIb autoimmune chronic spontaneous urticaria — is based on an updated Gell – Coombs classification of hypersensitivity . This group of patients forms anti-IgE receptor ( FcεRI ) antibodies ( that can be of immunoglobulin G [ IgG ] or immunoglobulin M [ IgM ] isotype ), which bind to and directly activate mast cells ( see figure 2 ). 23 Other immunological features
Chronic urticaria
Rates Lifetime prevalence of up to 20 % ( overseas data ) 10 The reported prevalence of chronic urticaria is 1.4-4.4 %
Chronic spontaneous urticaria more prevalent than CIndU 10
Age
Average duration
Persistence
Geography
Any age group , with a higher incidence noted in children under five 10 Average age of onset : chronic spontaneous urticaria 30-50 ; CIndU 20-35 10
More common in adult women . The incidence in children does not differ by sex 11
Less than one week
Approximately 8 % of new-onset acute urticaria persists to become chronic urticaria 12
All ethnicities , with some studies reporting increased prevalence in non- Caucasian populations 14
Chronic spontaneous urticaria : 1-4 years Dermographism : 2-12 years Cholinergic urticaria : 3-8 years Cold urticaria : 2-9 years 10
The reported rate of persistence of chronic spontaneous urticaria at five years ranges between 29 % and 71 % 13
Geographical differences have been noted , with higher prevalence of chronic urticaria in Asia compared with Europe and North America 11
Source : Zuberbier T et al 2022 22 , Kolkhir P et al 2022 10 , Fricke J et al 2020 11 , Eun SJ et al 2029 12 , Balp MM et al 2022 13 , Jadhav R et al 2021 14 , Confino-Cohen R et al 2012 15 , Magerl M et al 2016 16
in chronic spontaneous urticaria include upregulation of protease-activated receptors and Mas-related G protein – coupled receptors .
Stress-associated exacerbations are thought to be mediated by afferent nerves releasing substance P , which activates adjacent dermal mast cells . 24 Contribution from the extrinsic coagulation system , via activation of tissue factor , has also been suggested . 25
The pathogenesis of CIndU remains elusive , and further studies are needed . 16 Elevated histamine in patients ’ serum following episodes of CIndU suggests the final stage is indeed mast cell and basophil activation . 26 It is hypothesised that relevant environmental triggers induce expression of autoantigens in the skin , which then cause activation of tissue granulocytes . No autoantigens have been consistently identified . 27 In cold urticaria , evidence for IgE-mediated autoimmunity comes from studies showing transfer of cold sensitivity by transfusing serum from affected to healthy patients . 28 In cholinergic urticaria , acetylcholine appears to play an essential role . 29 Recent studies have identified that a muscarinic receptor ( CHRM3 ) on mast cells , and specific IgE to a sweat antigen ( MGL _ 1304 ) may contribute to granulocyte activation in cholinergic urticaria . 29
Non-histaminergic angioedema is an important differential diagnosis for isolated angioedema in the absence of weals . This condition is mediated by bradykinin excess , resulting in increased vascular permeability and plasma leakage . The archetypal example , HAE , is caused by quantitative or functional deficiency in C1-esterase inhibitor due to mutations in the SERPING1 gene . C1-esterase inhibitor deficiency leads to overactivation of the plasma kallikrein – bradykinin system , causing increases in tissue bradykinin and episodic angioedema . An acquired form of C1-esterase inhibitor deficiency can be caused by antibodies to the C1-esterase protein and functional reduction in levels . 30
Medications may also cause non-histaminergic angioedema . In susceptible patients , PAGE 22