Clinical review

Allergy and the skin. IUrticaria

Malcolm W Greaves,  Ruth A Sabroe. 

	Acute urticaria

Episodes of acute urticaria are common. Causes include type 1 hypersensitivity reactions to certain foods and drugs, including blood products. In up to 50% of cases a cause is not identified. The involvement of a particular food allergen can be confirmed by the radioallergosorbent test (RAST) and skin prick tests. Allergy to latex usually manifests as contact urticaria or with systemic symptoms but rarely presents with generalised urticaria. As with suspected reactions to peanuts it is recommended that tests for latex allergy be done in a hospital setting as severe systemic reactions may occur. Management of acute urticaria includes avoidance of the causative agent and treatment with H₁ antihistamines. A short course of prednisolone can be given for severe episodes of urticaria unresponsive to antihistamines.

	Chronic urticaria

Chronic urticaria is conventionally defined as the occurrence of daily or almost daily widespread itchy weals for at least six weeks. It occurs in at least 0.1% of the population and is much more troublesome than acute urticaria. Recent studies using an internationally recognised quality of life questionnaire, the Nottingham health profile, have highlighted the serious disability of patients with chronic urticaria, including loss of sleep and energy, social isolation, altered emotional reactions, and difficulties in aspects of daily living. The disability is of the same order as that experienced by patients with severe chronic ischaemic heart disease.

View larger version (78K): [in this window] [in a new window]   View larger version (121K): [in this window] [in a new window]   Dermographism induced with a calibrated, spring loaded dermographometer

Physical urticarias
The first step is to identify patients with physical urticarias. These are patients in whom wealing and itching is provoked at the sites of a physical stimulussuch as stroking the skin (dermographism), cooling the skin (cold urticaria), or sun exposure (solar urticaria). Cholinergic urticaria, a widespread transitory pruritic rash following exercise, emotion, or heat, also falls into this category.

View larger version (75K): [in this window] [in a new window]   View larger version (88K): [in this window] [in a new window]   View larger version (90K): [in this window] [in a new window]   Cold urticaria induced by placing an ice cube on the skin for 5 minutes Solar urticaria, which can be induced by irradiation of the skin with a solar simulator Cholinergic urticaria induced by brisk exercise

View larger version (82K): [in this window] [in a new window]   Mucocutaneous angio-oedema

Angio-oedema
Defined as deep mucocutaneous swellings, angio-oedema occurs concurrently with ordinary urticarial weals in about half of patients with chronic urticaria. Hereditary angio-oedema is a rare condition caused by an autosomal dominant inherited defect of the inhibitor of the first component of the complement cascade. Urticarial weals are not strictly a feature of hereditary angio-oedema, but if doubt exists, a normal value for the serum complement component C4 in between attacks effectively excludes this diagnosis in almost all cases.

Urticarial vasculitis
It is all too easy to overlook the occasional patient with urticarial vasculitis. The clinical picture of urticarial vasculitis may be distinctive, but more often the morphology of the weals resembles that of chronic urticaria and the only clinical clue is the duration of individual weals, which invariably persist for more than 24 hours. Confirmation of the diagnosis by a skin biopsy to show histological evidence of vasculitis is important because these patients need to be fully investigated for evidence of lupus erythematosus or other autoimmune connective tissue disease, and of renal or other internal organ involvement. They also usually require additional treatment measuresfor example, dapsone, colchicine, or occasionally oral steroids.

Pathogenesis
The weals in chronic urticaria are caused by a local increase in cutaneous vascular permeability, mainly in the postcapillary venules. This, and the associated erythema and itching, is evoked by pharmacological mediators released from mast cells in the skin. Histamine, stored in the granules of mast cells and secreted as a result of degranulation, is the principal mediator; this is evident from the symptomatic relief afforded by H₁ antihistamines. Experimental wealing due to intracutaneous injection of histamine is short lived, lasting minutes rather than hours. In contrast, individual urticarial weals last 12 or more hours. This is due to the actions of additional mediators, some of which are probably also derived from the mast cells. There are some similarities between the histopathological appearances of urticarial weals and those of the late phase response. This may suggest the additional participation of basophil leucocytes that contain histamine.

View larger version (34K): [in this window] [in a new window]   Investigation of chronic urticaria

Causes and investigation
Until recently the cause of chronic urticaria was unknown in nearly all cases. Today we still do not know the aetiology in many, but subsets of chronic urticaria can now be defined in which the cause can be identified, with important consequences for treatment.

Autoimmune chronic urticaria
In about 50-60% of patients with chronic urticaria the weals are caused by circulating histamine releasing factors. In half of these the histamine releasing activity has been proved to be due to IgG autoantibodies directed against epitopes expressed on the extracellular portion of the  subunit of the high affinity IgE receptor (FCRI), which is located on the outer surface of all mast cells and basophil leucocytes. This autoantibody, which is of isotype IgG₁ or IgG₃, is functional because it releases histamine from mast cells or basophils in vitro and causes wealing upon intradermal injection in humans in vivo. Anti-FCRI autoantibodies cross link  subunits of adjacent FCRI, thereby triggering release of histamine. In a very small minority of such patients the autoantibody has proved to be an IgG anti-IgE autoantibody, but the result seems to be the same.

View larger version (23K): [in this window] [in a new window]   Probable pathogenesis of wealing in autoimmune (anti-FCRI) chronic urticaria. Activation of cutaneous mast cells by anti-FCRI autoantibodies leads to release of proinflammatory mediators and also to activation of eosinophils (via interleukin 5) and immunoglobulin-synthesising B lymphocytes (via interleukin 4 and interleukin 6)

Natural course
Characteristically, chronic urticaria pursues a course of remission and relapse, relapses being triggered by intercurrent infections, stress, drugs (especially aspirin and angiotensin converting enzyme inhibitors), and the menstrual cycle. It has been estimated that about 50% of patients presenting with a history of chronic urticaria of at least 3 months' duration will still have the condition three years later.

Treatment
Patients should be advised to avoid factors that trigger relapses, especially non-steroidal anti-inflammatory drugs. As weals tend to occur at sites of local pressure, tightly fitting clothes, belts, and shoes should be avoided. Itching is exacerbated by warmth, and therefore a cool ambient temperature, especially in the bedroom, is helpful and may prevent insomnia.

Systemic steroids are not indicated in chronic urticaria owing to the substantial doses required, the development of tolerance, and frequency of chronic steroid toxicity. In exceptional circumstances, however, short tapering courses of prednisolone have a place when rapid control over a limited period is required.

	Acknowledgments

St John's Institute of Dermatology provided the first five photographs in the article. The photograph showing mucocutaneous angio-oedema is published with permission of the patient, whose grandson, Robert Payne, provided the photograph.

Malcolm W Greaves is head of clinical dermatology and Ruth A Sabroe is honorary senior registrar at the professorial unit, St John's Institute of Dermatology, St Thomas's Hospital, London.

The ABC of allergies is edited by Stephen Durham, honorary consultant physician in respiratory medicine at the Royal Brompton Hospital, London. It will be published as a book later in the year.    BMJ 1998;316:1147-50