Guest Editorial
U r t i c a r i a

Gordon L. Sussman*


Urticaria is a common problem seen in everyday prac-tice causing much frustration, anxiety, and morbid-ity in affected patients. By clinical description it is a typical wheal and flare response characterized by blanchable, ery-thematous, and edematous cutaneous lesions. The size of individual wheals can vary from 1 mm to 2 mm to several c e n t i m e t res in diameter. Urticarial lesions are usually tran-sient and infrequently persist longer than 24 to 48 hours. Often associated with urticaria is a deeper subcutaneous swelling called angioedema.

Single or recurrent episodes of hives lasting <6 weeks are called acute urticaria. This is the most common type a ffecting about 15% of the population. A cause can be iden-tified in >60% of these cases. In contrast, chronic urt i c a r i a is defined as hives occurring at least three times a week for longer than 6 weeks. A cause is rarely identified, hence the term “chronic idiopathic urticaria.”

Mast cells play a central role in the pathophysiology of urticaria. When activated, mast cells release potent inflammatory mediators into the extracellular cutaneous compartment. The primary process of degranulated mast cells is edema due to increased capillary and venular per-m e a b i l i t y. Surrounding vasodilatation results from cutaneous a n t i d romic neurostimulation with the release of substance P causing reflex erythema. The stimulation of free nerve end-ings is responsible for the primary symptom of itching and burning.

Mast cell mediators may be released by a number of different mechanisms. Immunologic activation may occur when IgE antibodies bound to the mast cell surface recep-tors are bridged by specific allergen. Complement activa-tion results in split products, the so-called anaphylatoxins, which can also activate mast cells. Nonimmunologic medi-ator release can be caused by some drugs including the opi-ates and general anesthetic agents. Other examples include n e u ro h o rmones and cellular histamine-releasing factors derived from various inflammatory cells. The consequence of mast cell degranulation includes an early-phase re s p o n s e characterized by edema, vasodilatation, and smooth mus-cle constriction. A late-phase inflammatory response is characterized by the influx of eosinophils and neutrophils seen at 8 hours that is followed by a mononuclear cell infil-tration seen at 24 to 28 hours.

However, this is only the tip of the iceberg. The com-plexity of urticaria is currently beginning to be more com-pletely appreciated. At one time histamine was thought to be the most important, if not the only mast cell mediator. After all, intradermal histamine injection could exactly re p roduce a local response of hives. However, clinically we knew that H 1 -antagonist treatment was often suboptimal. This pointed to non-histamine mast cell mediators as being pathogenically important. Newly formed mediators included p rostaglandins, leukotrienes, and platelet activating factor. Some of these mediators were responsible for this late inflammatory response.

Recently, it has been recognized that at least a subset of chronic idiopathic urticaria and angioedema was due to an autoimmune process. The presence of thyroid autoim-munity first pointed to this association. Other autoim-mune diseases occurring with urticaria included vitiligo and pernicious anemia. Upon intradermal injection of autolo-gous serum, a wheal and flare response was reported to occur, which persisted for 8 hours. This histamine releas-ing factor was found to be due to the presence of autoan-tibodies with functional pro p e rties of anti-IgE. This autoantibody was characterized to be an IgG dire c t e d against the alpha subunit of the high-affinity IgE receptor. This has been confirmed by other laboratories. A virus, dru g , or other putative target antigen may be responsible for incit-ing this autoimmune process.

In the evaluation of urticaria, taking a careful history, is the most important aspect. It is important to remember to search for allergens such as foods and drugs, and to inquire about infections and physical stimuli as being pre-cipitating causes. The physical examination will provide clues for further investigations. Extensive laboratory test-ing is expensive, time-consuming, and is not cost eff e c t i v e . Physical challenges are useful to identify patients with associated physical urticaria. Skin testing should only be used to confirm the history. Skin biopsy is reserved for patients with atypical urticarial lesions to rule out a necro-tizing vasculitis.

In the treatment of urticaria, all patients should be coun-seled to avoid specific aggravating factors, be it foods or d rugs. Aspirin and functionally related pro s t a g l a n d i n inhibitors are often triggers of urticaria. A strict elimina-tion diet may be tried but generally this is not useful. If it is used it should be done so for only short periods of time.

H 1 antagonists are still the cornerstone for safe, chro n i c t reatment. Options for first line treatment generally include nonsedating antihistamines. Occasionally sedating, first generation antihistamines may also be used. It is import a n t to ensure patient compliance, possibly by doing histamine skin testing.

Other therapeutic options in the treatment of urt i c a r i a may include the addition of an H 2 antagonist such as cime-tidine. This may be useful only in combination with the H 1 antagonist, possibly because the effect is due to a drug inter-action with increased levels of the H 1 antagonist. Doxepin may be useful if adequate dosages can be administered. Alter- native antiinflammatory medications that have been occa-sionally re p o rted to be effective include stanazolol and danazol, hydro x y c h l o roquine, and dapsone. Rare l y, severe re f r a c t o ry chronic urticaria, unresponsive to other measure s , may require treatment with oral corticosteroids; however, this treatment should be used only for short periods of time (maximum duration two to three months) and considera-tion to using an alternate-day oral protocol should be attempted.

In summary, urticaria is the common manifestation of diverse pathophysiologic mechanisms and processes. Mast cell degranulation and the release of potent mediators lead to urticaria. There may be an immediate vasoactive effect, but the late or delayed inflammatory phase is probably the most important consequence of mast cell release and may be responsible for the vasculitis observed in about 50% of chronic urticaria patients. In addition, a subset of chronic idiopathic urticaria and angioedema probably re p resent an autoimmune disease. The treatment depends on the specific subgroup identified and should improve with the intro-duction of new mast cell stabilizers, mediator antagonists, and novel immunologic treatments.

Received 12/02/99. Accepted for publication 12/13/99.

*Associate Pro f e s s o r, Department of Medicine, University of To ro n t o and Head, Section of Allergy, Division of Immunology, St. Michael’s Hospital, Toronto, Ontario, Canada

Reprint requests: Gordon L. Sussman, MD, 202 St. Clair Avenue We s t , Toronto ON Canada M4V 1R2

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