Mast cells and mast-cell mediators long have been implicated as being important in the pathogenesis of urticaria. Evidence includes the morphologic and histologic definition of mast-cell degranulation after specific physical stimuli in patients with physical urticarias; wheal and flare formation after intracutaneous injection of mast-cell mediators; identification of mediators in biological fluids collected during urticarial reactions; and the ability to suppress the urticarial tissue response with specific mediator antagonists (e.g., antihistamines). Moreover, evidence of mast-cell degranulation is seen in chronic urticarial lesions, and the skin of patients with chronic urticaria often contains increased numbers of mast cells.

Overall, mast cells and mast cell–dependent mediators play a prominent role in the pathogenesis of urticaria and angioedema. A number of mediators other than histamine, however, are important in causing urticaria and angioedema (see Box 421.1). Therefore, selective H₁ antihistamines seldom are entirely effective in treating urticarial reactions. Studies of the role of mediators other than histamine in the pathogenesis of urticaria should aid in the development of new and better treatment modalities for this disorder. For example, because leukotrienes can induce wheal and flare responses and have chemotactic activity, leukotriene modifiers have been used in treating chronic urticaria.

Although mast cells and mast-cell mediators are central to the pathogenesis of urticaria and angioedema, the presence of IgE antibodies to specific allergens is not necessary. A number of mechanisms other than classic allergic reactions may lead to mast-cell degranulation. The activation of either the classic or alternative complement pathways may cause urticaria by producing anaphylatoxins (C3a, C4a, C5a), which can degranulate mast cells. A number of drugs, including opioids, some antibiotics, and nonsteroidal antiinflammatory agents, may lead to nonimmunologic mast-cell mediator release. Neuropeptides (discussed later) also can cause mast-cell degranulation. Inflammatory reactions resulting in the production of histamine-releasing factors from lymphocytes, macrophages, and neutrophils may cause mast-cell mediator release as well. Such physical stimuli as heat, cold, and pressure can cause mast-cell mediator release and urticaria in susceptible individuals. Thus, many potential mechanisms lead to mast-cell mediator release and urticaria.

Studies have shown that the intradermal injection of autologous serum produces a wheal and flare reaction in approximately 60% of patients with chronic idiopathic urticaria, implying a role for circulating histamine-releasing factors. These patients can be subdivided into two groups of similar size. One group has heat-stable nonimmunoglobulin mediators that release histamine from mast cells but not from basophils. Another group has IgG autoantibodies to the high-affinity IgE receptors or IgE, or both, that are capable of inducing histamine release from both mast cells and basophils. Patients with this autoantibody have been shown to have an increased incidence of HLA-DR4, Hashimoto’s thyroiditis, and antimicrosomal antibodies, thus implying that, in a subset of patients, chronic idiopathic urticaria is an autoimmune disorder. Patients often have a positive skin test to autologous serum injected intradermally and read at 30 minutes. Novel therapies for this subgroup of patients have included plasmapheresis, intravenous immune globulin, and cyclosporine.

The exact role of neuropeptides in chronic urticaria and physical urticarias is unclear. However, the proximity of mast cells to sensory nerves favors their involvement. The intradermal injection of many neuropeptides results in erythema and a wheal or induration that closely resembles an urticarial lesion. These neuropeptides are present in skin and have direct effects on cutaneous vasculature, including vasodilation and edema. The physical urticarias exhibit some evidence that neuropeptides might be important. The provocative stimuli in these conditions
include such factors as cold, heat, and pressure, which are expected to activate neuropeptide-containing sensory nerve fibers in the skin. The release of these neuropeptides then can cause vasodilation and edema directly. Several neuropeptides, including substance P, also can degranulate cutaneous mast cells. Repeated topical application of capsaicin, a substance that depletes neuropeptides from afferent nerves, has prevented the urticarial response to thermal challenge in patients with cold- and heat-induced urticaria.

Numerous biopsy studies suggest that inflammatory cells other than mast cells play important roles in urticaria as well. Often, chronic urticarial lesions are characterized by a non-necrotizing perivascular infiltrate composed of CD4⁺ T lymphocytes and monocytes. Neutrophils are predominant in a minority of lesions. Because lymphocytes, monocytes, and other cells release histamine-releasing factors, and mast cells may produce substances that activate T cells and monocytes, one might envision a cyclic propagation of an event initiated by mast-cell degranulation. Corticosteroids work, in part, because T lymphocytes and monocytes likely play a role in the pathogenesis of chronic urticaria. Corticosteroids have not been shown convincingly to inhibit cutaneous mast-cell degranulation and, therefore, generally have not been shown to be effective in the immediate-onset physical urticarias in which cellular infiltrates usually are not noted by biopsy. In general, chronic urticarial lesions contain no evidence of complement or immunoglobulin deposition.

Drug reactions are one of the most common causes of urticaria and angioedema. The reactions are mediated by type I or type III immune mechanisms or by direct nonimmunologic mast-cell mediator release. Depending on the mechanisms involved, the urticaria may occur immediately or at days to weeks after drug exposure (e.g., serum sickness syndrome with urticaria). Many drugs are associated with urticaria. Antibiotics, especially penicillin and related compounds, remain the leading causes of drug-induced urticaria. Aspirin and other nonsteroidal antiinflammatory agents are common causes of urticaria. Some data indicate that aspirin and nonsteroidal antiinflammatory drugs may exacerbate chronic urticaria in selected patients. Some drugs, such as the opioids, can cause mast-cell degranulation directly. Other classes of drugs frequently associated with urticaria include diuretics, radiocontrast dyes, muscle relaxants, and sedatives or barbiturates. All drugs taken by affected patients must be identified, because any drug can be a potential cause of urticaria. Vitamins, lotions, contraceptives, laxatives, and various over-the-counter drugs represent possible offenders. When a drug reaction is suspected, all unnecessary drugs should be eliminated, and an attempt should be made to switch to alternative, chemically distinct forms of necessary drugs. Blood products may cause urticaria through complement-mediated effects.