Aetiology

Acute urticaria

Many cases of acute urticaria and/or angio-oedema are allergic in nature and caused by an immunoglobulin E (IgE)-mediated reaction. The most common agents involved are drugs and foods (e.g., milk, eggs, peanuts, tree nuts, finfish, shellfish). Insect bites/stings or contact with other allergens (e.g., animal dander) can also lead to acute urticaria and/or angio-oedema.

Drugs may trigger urticaria through an IgE-mediated allergic reaction (e.g., beta-lactam antibiotics) or through direct mast cell degranulation (e.g., non-steroidal anti-inflammatory drugs [NSAIDs], aspirin, opioids, vancomycin).[2] Viral infections and radiocontrast dye trigger acute urticaria through non-IgE-mediated mechanisms.

Chronic urticaria

The aetiology of chronic urticaria and/or angio-oedema is complex and incompletely understood. Less than 10% of patients have inducible urticaria, where symptoms develop in response to a predictable trigger. Food and drugs rarely cause chronic urticaria. Chronic inducible urticaria may be triggered by heat, cold, pressure, sunlight, vibration, acetylcholine release, and water.[1]​​

The majority of patients with chronic urticaria, with or without angio-oedema, experience spontaneous, unpredictable lesions. Approximately half of these cases are thought to be autoimmune/antibody associated in nature, owing to the presence of IgG antibodies to the high-affinity IgE (Fc epsilon) receptor or to IgE, which are able to activate mast cells.[14]

Although the presenting features and management of individuals with autoimmune/antibody-associated urticaria are similar to those for individuals with idiopathic urticaria, the former tend to have a more protracted course.

A minority of cases of chronic, spontaneous urticaria occur in association with an autoimmune disease, such as Hashimoto's thyroiditis or systemic lupus erythematosus.[15][16]

Urticaria can occur as a manifestation of unusual conditions, such as exercise-induced anaphylaxis, urticaria pigmentosa, or systemic mastocytosis.

Angio-oedema without urticaria

A study of 776 patients (with angio-oedema without urticaria) attending an angio-oedema clinic found that 25% of cases are hereditary; 11% are caused by ACE inhibitors; 23% are caused by autoimmune disease, other drugs, insect bites, or food; and 41% are idiopathic.[17]

Hereditary angio-oedema (HAE) is caused by mutations in the SERPING1 gene, which codes for C1 inhibitor. It is inherited in an autosomal dominant manner, although 25% of cases are due to new mutations and do not have a positive family history.[18] In all, 85% of cases are caused by a deficiency of C1 esterase (type 1 HAE) and 15% of cases are caused by C1 esterase dysfunction (type 2).[12]

Pathophysiology

Urticaria with or without angio-oedema

Acute or chronic urticaria is caused by the release of bioactive mediators from mast cells and basophils, after activation of either the innate or the adaptive immune system.[6]

Mast cells are distributed throughout the body, including within the dermis, subdermis, and mucosal surfaces. When mast cells are activated, degranulation leads to a rapid release of preformed vasoactive mediators such as histamine, leukotriene C4, and prostaglandin D2.[19] The release of these mediators leads to vasodilation, increased vascular permeability, and sensory nerve activation. This manifests clinically as oedema and pruritus.

A second, delayed release of inflammatory cytokines (tumour necrosis factor, interleukin-4, interleukin-5) accounts for an inflammatory infiltrate and longer-lasting lesions.

Biopsies of skin lesions reveals a dense peri-vascular inflammatory infiltrate consisting of CD4+ lymphocytes, eosinophils, basophils, and neutrophils.[20] A minority of cases show evidence of urticarial vasculitis with vascular destruction, necrosis, or immune complex deposition.[21]

Angio-oedema without urticaria

Angio-oedema may be histamine-mediated or bradykinin-mediated.

Histamine-mediated angio-oedema is caused by the same mast cell and basophil processes responsible for urticaria. Most patients with idiopathic acquired angio-oedema have histamine-mediated angio-oedema and respond well to antihistamine treatment.[12]

Bradykinin-mediated angio-oedema is caused by aberrant activation of the contact-kinin system and is the predominant mechanism responsible for hereditary angio-oedema and ACE inhibitor-induced angio-oedema.[22] In the contact-kinin system, coagulation factor XII is activated by negatively charged surfaces (e.g., activated platelets).[23] Activated factor XII converts plasma prekallikrein to kallikrein, and kallikrein converts high molecular weight kininogen to bradykinin. Bradykinin binds to the bradykinin B2 receptor expressed on endothelial cells and triggers an increase in vascular permeability.[22]

Various enzymes, including angiotensin-converting enzyme (ACE), break down bradykinin.[11] C1 esterase inhibitor, a component of the complement system, inhibits the conversion of prekallikrein to kallikrein and also inhibits the cleavage of high molecular weight kininogen to bradykinin.[24]

Patients with a deficiency of functional C1 esterase inhibitor therefore have increased production of bradykinin, and patients taking ACE inhibitors have reduced breakdown of bradykinin. Bradykinin causes vasodilation and increased vascular permeability, leading to angio-oedema.[11] Patients very often have low C4 levels, because lack of C1 esterase inhibitor leads to activation of the classical complement pathway.

Acquired angio-oedema can be caused by an acquired C1 esterase inhibitor deficiency. This almost always occurs after age 40 and is mediated by neutralising autoantibodies to C1 esterase inhibitor.[12] It often occurs in association with lymphoproliferative disease such as non-Hodgkin's lymphoma or monoclonal gammopathy of uncertain significance.[25]

Classification

Clinical classification

Acute urticaria

  • Episodes occur over less than 6 weeks and are generally self-limiting.

  • Causes typically include hypersensitivity reactions (drugs, foods, insect bites or stings), contact reactions (environmental allergens such as grass, animal saliva, latex), or immune complex disease (post-viral, serum sickness).

  • Episodes without an identifiable cause are termed idiopathic.

Chronic urticaria

  • Recurrent episodes of urticaria on a nearly daily basis for 6 weeks or longer.

  • The aetiology is most often idiopathic.

  • Foods and drugs rarely cause chronic urticaria.

  • Chronic urticaria can sometimes be associated with autoimmune disease.

  • Although duration can be months or even years, spontaneous resolution is typical.

Inducible urticaria

  • Inducible urticaria (formerly known as physical urticaria) accounts for 15% to 20% of cases of urticaria.[4]

  • Sub-types include dermatographism, cholinergic, delayed pressure, sunlight (solar), cold, vibratory, and water (aquagenic).

Angio-oedema

  • Angio-oedema is swelling involving the deeper layers of the subdermis.

  • Angio-oedema can occur with or without urticaria, and can occur in both the acute and the chronic setting.

  • Hereditary angio-oedema, drug-related angio-oedema, and acquired angio-oedema occur without urticaria.

Other

  • Urticaria can be a manifestation of unusual conditions, such as exercise-induced anaphylaxis, urticaria pigmentosa, or systemic mastocytosis.

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