Etiology, Classification, and Treatment of Urticaria

Histologically, the 2 groups of urticaria are indistinguishable.6 Advanced techniques show a perivascular nonnecrotizing infiltrate of CD4⁺ lymphocytes consisting of a mixture of T_H1 and T_H2 subtypes, plus monocytes, neutrophils, eosinophils, and basophils. These cells are recruited because of interactions with C5a, cell priming cytokines, chemokines, and adhesion molecules.⁶ A recent study also found inflammatory cells and mediator up-regulation in uninvolved CIU skin as a sign of prolonged and widespread "urticarial status."¹²

Physical Urticaria

Physical urticaria are classified and induced by a physical stimulus. Most physical urticaria occur within minutes of provocation and resolve within 2 hours, with the exception of delayed pressure urticaria, which may persist for 24 hours or longer.¹³ Angioedema may occur in all physical urticaria except dermographism. Overlap between groups is common, and physical urticaria often occur as an added feature of chronic urticaria.

The most common type of physical urticaria is simple immediate dermographism, presenting with linear wheals at sites of scratching or friction. It occurs in about 1.4% to 5% of the population worldwide¹⁴ and may be viewed as an exaggerated physiologic response. On average, dermographism runs a course of 2 to 3 years before usually resolving spontaneously.¹⁵

Delayed-pressure urticaria is a response to sustained pressure to the skin, presenting with deep erythematous edema after a delay of unknown cause lasting 30 minutes to 12 hours.^14,16 An increased level of interleukin 6 has been found in suction blister fluid over induced lesions.^2,15 The edema tends to be deeper, pruritic, and painful, and it may persist for days. Systemic features such as malaise, flulike symptoms, and arthralgia may occur. The prognosis is variable, but the mean duration is 6 to 9 years.¹⁷ The response to antihistamines often is poor, and oral corticosteroids may be needed for disease control.²

Cholinergic urticaria usually presents with multiple, transient, pruritic, small, red macules or papules on the neck, trunk, forearms, wrists, and thighs in response to heat, often surrounded by an obvious flare. It mainly affects young adults, with an overall prevalence of 11% in this group.¹⁸ Fifty percent of patients are atopic.¹⁵ Angioedema and systemic manifestations such as headache, palpitations, abdominal pain, wheezing, and syncope may occur. The cholinergic sympathetic innervation of sweat glands is involved because the eruption can be blocked by topical anticholinergic drugs,¹⁹ but how this leads to urticaria is unclear. The routine treatment is with low-sedation H₁-type antihistamines, with or without an anxiolytic such as oral propranolol. In severe cases, the anabolic steroid stanazolol has been used.¹⁵

Cold urticaria is a heterogeneous condition in which whealing occurs within minutes in response to cold exposure, most frequently in children and young adults. Wheals usually arise at the site of localized cooling but may be generalized following lowering of the body temperature.¹⁶ Diagnosis may be confirmed by applying an ice cube for 5 to 15 minutes to the skin, allowing an interval for skin rewarming, and observing the development of whealing that occurs on skin rewarming. Systemic symptoms such as flushing, headache, abdominal pain, and syncope can occur if large areas are affected. The cause is unknown, but a serum factor, possibly IgM or IgE, has been implicated.²⁰ A heterozygous deficiency of the protease inhibitor α1-antichymotrypsin has been demonstrated and may be etiologically important in some patients.²¹ The prognosis is good, with spontaneous improvement in an average of 2 to 3 years.¹⁵ Ninety-six percent of cases of cold urticaria are primary.²² The diagnosis of secondary acquired cold urticaria depends on being able to demonstrate cryoglobulins, cold agglutinins, or possibly cryofibrinogens.¹⁷ These findings should, in turn, lead to investigations for an underlying cause, such as hepatitis B or C infection, lymphoproliferative disease, or infectious mononucleosis.¹⁵

Other uncommon forms of physical urticaria include adrenergic urticaria, which develops during phases of stress and has been associated with an increase in the plasma concentrations of norepinephrine, epinephrine, and prolactin.²³ Aquagenic urticaria is precipitated by skin contact with water of any temperature.³ Exercise-induced anaphylaxis involves urticaria, respiratory distress, or hypotension after exercise. In localized heat urticaria, wheals occur on skin in direct contact with warm objects. Solar urticaria is a rare condition that occurs within minutes of exposure to UV light waves ranging from 280 to 760 nm¹⁴; it usually disappears in less than one hour. Vibratory urticaria occurs after a vibratory stimulus and can be a hereditary autosomaldominant disorder or an acquired sporadic disease.²⁴

Urticarial Vasculitis

Urticarial vasculitis describes a distinct entity in which the gross cutaneous lesions resemble urticaria and histologically show features of a vasculitis. The diagnosis is suggested clinically by wheals lasting more than 24 hours and residual bruising.²⁵ Although the clinical lesions may present as typical urticaria, pathophysiologically, it is a different disease caused by deposition of antigen-antibody complexes in vessel walls, a type 3 reaction causing vascular damage.¹⁷ Lesions often occur at pressure points and may resolve with residual purpura. Extracutaneous manifestations include transient and migratory arthralgia (50%); gastrointestinal symptoms (20%); and pulmonary obstructive disease (20%), particularly in smokers and patients with renal disease (5%–10%).¹⁷ Normocomplementemic urticarial vasculitis usually is idiopathic, but hypocomplementemic urticarial vasculitis may be associated with underlying systemic lupus erythematosus, Sjögren syndrome, or cryoglobulinemia.² Primary urticarial vasculitis can occasionally evolve into systemic lupus erythematosus.²⁶ Patients with urticarial vasculitis often improve on nonsteroidal anti-inflammatory drugs (NSAIDs), but some patients may need immunosuppressive therapy.