Introduction

Urticaria, often called "hives", refers to a skin eruption consisting of raised demarcated intensely itchy papules or weals. While urticaria involves dermal swelling, angioedema is due to oedema in the deeper subcutaneous and submucosal tissues, especially involving the palms of the hands, soles of the feet, head, and neck. Angioedema of the throat may cause respiratory obstruction in severe cases. Urticaria/angioedema has been arbitrarily defined as ‘Acute’ if it lasts less than 6 weeks, with more prolonged cases of relapsing skin swellings being labelled as ‘Chronic’. Up to 50% of cases of urticaria are associated with angioedema, and up to 25% of the population will develop one of these problems during their lifetime.

Tissues involved in urticaria/angioedema reveal dermal or subcutaneous oedema in association with a perivascular infiltrate of T-lymphocytes, macrophages, eosinophils and mast cells which may be sparse and fleeting in acute cases or more extensive in chronic urticaria. The swelling and itch seen in urticaria/angioedema is due to mast cell degranulation. The triggers include a variety of factors (Table 1). However, in up to 50% of cases of acute and chronic urticaria/angioedema, no cause is identified. Some physical urticarias involve structural modification of the IgE molecule by various physical factors, and are IgE-mediated.

While IgE-mediated processes tend to occur rapidly after exposure to minute antigen doses, direct mast cell degranulation is often delayed for a few hours and is dose-dependent, often requiring a threshold to be exceeded before symptoms occur. This threshold may be lowered by other concurrent factors, such as medications (eg. aspirin), alcohol, viral infections, and exercise. A careful clinical history is therefore paramount.

Acute Urticaria

Acute urticaria occurs commonly in children and young adults, often as an immediate response to clearly identifiable agents, such as foods or drugs (Table 1). Reactions to both ingestion and skin contact may occur, particularly in atopic subjects. For example, contact urticaria in response to aeroallergens such as grass pollens may occur in patients with respiratory allergic symptoms to these agents. Complement-mediated mast cell degranulation following immune complex formation is a well-recognised prodromal feature of Hepatitis B and Epstein-Barr infections. Life-threatening angioedema reactions may occur with angiotensin-converting enzyme inhibitor therapy, but these reactions do not seem to be as common with angiotensin-II blockers.

Chronic urticaria is a seriously disabling condition, with insomnia, fatigue, social isolation and mood alterations causing a significant degree of dysfunction to many patients. While up to 50% of patients with chronic urticaria have no identifiable cause for their problem, many cases will be found to have food chemical intolerance as a significant contributor. A history of urticaria developing in response to aspirin is a strong clue to possible chemical intolerance. Agents involved in chemical intolerance include salicylates, nitrites, benzoates, sulphites, and food colourings.

About 8% of patients with systemic lupus erythematous (SLE) initially present with urticaria. SLE should be considered in patients with chronic urticaria, especially if other clinical features suggestive of systemic autoimmunity are present. Autoimmune thyroiditis can be associated with chronic urticaria, and should be tested for in the appropriate clinical context. A recent spate of reports have suggested that Helicobacter pylori (H. pylori) infection may be implicated in some cases of urticaria, with antibiotic therapy resolving the condition. Serological screening for H. pylori is probably only indicated if there are associated dyspeptic symptoms. Other systemic disorders associated with urticaria include rheumatoid arthritis, systemic sclerosis, and chronic infections, but in practice these conditions are found only rarely and should only be investigated if there are other suggestive clinical features.

Hereditary angioedema is an autosomal dominant condition where physical and emotional trauma provokes episodes of angioedema from early life. These patients do not develop urticaria. They are diagnosed by reduced C4 levels and reduced functional activity or levels of C1-esterase-inhibitor.

Physical urticarias should be assessed on history (Table 2). Examples include urticaria seen in response to skin stroking (dermatographism), cooling (cold urticaria), or solar irradiation (solar urticaria).

Autoimmune Chronic Urticaria

Up to 60% of patients with chronic urticaria have demonstrable histamine-releasing activity in their serum, due to a heterogeneous group of molecules such as IL-1, IL-3 and GM-CSF released from activated lymphocytes, monocytes, neutrophils and fibroblasts. 50% of these patients with histamine-releasing activity have IgG autoantibodies directed against epitopes on the extracellular portion of the a -subunit of the high-affinity IgE receptor (Fce R-Ia ) on the surface of mast cells and basophils. Rarely, the autoantibodies are targeted directly against IgE molecules. While these patients have an identical clinical presentation to antibody-negative cases, the identification of patients with autoimmune urticaria may be of therapeutic utility, as some of these patients with severe disabling disease have responded to immunomodulation with intravenous immunoglobulin or plasmapheresis.

Uncommonly, urticaria may reflect underlying vascultis secondary to autoimmune conditions, particularly SLE. Clinical clues to the presence of such conditions are indicated in Table 3. Investigations reveal evidence of inflammation (raised erythrocyte sedimentation rate and C-reactive protein), with or without hypocomplementaemia, and biopsy of fresh lesions reveals a perivascular inflammatory infiltrate with leucocytoclasis and positive immunofluorescent staining for immunoglobulins and complement.

Acute transient urticarias do not require further investigation, although the clinical diagnosis of immediate hypersensitivity reactions to foods and drugs may be supported by positive skin-prick tests or the measurement of in-vitro specific IgE antibodies directed to relevant antigens.

As mentioned above, chronic urticaria has been associated with a large list of conditions, and screening for all of these would not be practical or useful. If physical urticarias are suspected, the appropriate diagnostic procedures listed in Table 2 should be performed. Initial relevant investigations for patients with urticaria of uncertain cause are listed in Table 4, with further tests such as anti-nuclear antibodies and viral or bacterial serology being indicated in the appropriate clinical setting.

If food additive intolerance is suspected, a formal two week exclusion diet should be performed, with a food and symptom diary being kept over this period. If symptoms improve, a double-blind placebo-controlled capsule challenge with various chemical agents must be undertaken to identify the causative agent for elimination.

The measurement of IgG anti-Fce R-Ia antibodies and IgG anti-IgE antibodies is in its infancy, and is currently not offered outside the research arena.

Chronic urticaria pursues a relapsing and remitting course, with exacerbations often triggered by intercurrent infections, stress, menses, and drugs (especially non-steroidal anti-inflammatory agents (NSAIDs), aspirin, angiotensin-converting enzyme inhibitors (ACEIs), and alcohol). About 50% of patients with chronic urticaria of at least 3 months’ duration will continue to have the condition three years later.

Treatment

Appropriate treatments have been indicated in Table 5. Corticosteroids are generally not indicated because of the prohibitive effects of steroid toxicity in the management of this chronic disease. Anecdotal reports have suggested that b 2-agonists (eg. terbutaline), calcium blockers (eg. nifedipine) and anabolic steroids (eg. stanazolol) may be helpful in selected cases, but no systematic randomised trials have been performed. Immunomodulation has been successfully used in patients with autoimmune chronic urticaria, using plasmapheresis, intravenous immunoglobulin, and cyclosporin A.

References

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