Case Report

A 55-year-old woman presented with complaints of urticaria, having recently changed medical groups. She developed acute tightening in the throat with difficulty breathing 7 years ago and was diagnosed with angioedema and treated with corticosteroids. She suffered from episodes of fever associated with itchy skin with a diffuse rash on her body on almost a daily basis. Her symptoms abated after a few months, and she was treated with prednisone 20 mg per day for the next six years which controlled her symptoms. For the past year, she was maintained on antihistamines only and reported occasional skin rash, episodes of stuffy nose and rhinorrhea, and one episode of chest wheezing.

The patient did not drink or smoke. Her family history was negative for connective tissue disease. She did not use any other medications on a regular basis, and there were no known allergies. Review of systems was unremarkable. Physical exam showed a diffuse erythematous maculopapular rash involving the trunk and both upper and lower extremities. There was no dermatographia. CBC with differential, LFT's, thyroid function tests, electrolytes, BUN, creatinine, and chest x-ray were all normal. Rheumatoid factor and ANA were also negative. On skin biopsy, chronic perivascular inflammatory infiltrate was seen at the superficial and mid dermis consistent with a diagnosis of dermal urticarial allergic reaction. No vasculitis was seen. Due to frequent recurrence of urticarial episodes, she was started on prednisone. Her condition is currently controlled with a low daily dose of 2 mg prednisone in addition to loratidine in A.M. and hydroxyzine in P.M.

Discussion

Urticaria, also known as hives or wheals, is a distinctive skin rash in reaction to various stimuli. Lesions vary in size from 2 mm edematous papules as in cholinergic urticaria to giant hives, a single lesion which may cover almost an entire extremity. They also vary in shape which may be round, oval, polycyclic when confluent, irregular or with pseudopodia. The border may be reabsorbed giving the appearance of incomplete rings. They vary in color, which may be uniformly red or white, or the edematous border may be red and the remainder of the surface white as in superficial hives. Thicker hives mostly have a uniform color. Hives may be surrounded by a clear or red halo. They may be thin and superficial or thick and firm from massive transudation of fluid into the dermis and subcutaneous tissue when it would be referred to as angioedema seen in lips, larynx and GI. At least 50% of patients with chronic urticaria also have angioedema. The distribution varies from being diffuse and haphazard in the idiopathic cases to a specific characteristic distribution in secondary cases such as in physical urticaria. Hives itch but the intensity varies. Some patients with a widespread eruption may experience little itching. Generally, pruritus is milder in deep hives because the edema occurs in areas with fewer sensory nerve endings than those near the surface of the skin.

Hives may occur at any age. Up to 20% of the population will have at least one episode. The majority of cases are acute episodes lasting from hours to a few weeks, and most patients do not seek medical attention. Chronic urticaria is defined as hives occurring daily or almost daily and lasting longer than six weeks.¹ It can be idiopathic or secondary to another pathological condition.² Chronic idiopathic urticaria occurs in 0.1% of the population and 20% may have the disease for more than 20 years.¹

Urticaria can result from many different stimuli on an immunologic or non-immunologic basis. The most common immunologic mechanism is hypersensitivity mediated by IgE. Another involves activation of the complement cascade. In some cases, there are autoantibodies directed against mast cell IgE receptors with histamine releasing activity.³ Common causes include foods, food additives, drugs, inhalants, hormones, chemical contacts, physical stimuli, systemic diseases, skin diseases, and genetic conditions.^4-15 (Table 1) There is no convincing evidence of the involvement of H. pylorior parasitic infestation as a direct cause of chronic urticaria, although there may be an indirect role.

If no cause is found after investigation of abnormalities elicited during the history and physical examination, there is little chance that it will be determined. The patient needs to understand that the course of this disease is unpredictable. It may last for months to years with an average of 3 to 5 years. In many cases, the disease resolves spontaneously. Patients who understand the nature of the disease may be less apt to go from physician to physician seeking a cure.

It is also important to distinguish idiopathic chronic urticaria from urticarial vasculitis. Urticarial vasculitis is characterized clinically by urticarial skin lesions and histologically by necrotizing vasculitis with immune complex deposition in the post capillary venules. Many patients have minimal signs or symptoms of systemic disease. One study of 72 patients with urticarial vasculitis found that systemic symptoms included angioedema (42%), arthralgias (49%), pulmonary disease (21%), and abdominal pain (17%).¹⁶ About one-third of the patients had hypocomplementemia. Sixty-four percent had lesions that lasted more than 24 hours. Thirty-two percent had painful or burning lesions and 35% had lesions that resolved with purpura. Patients with hypocomplementemia were more likely to have systemic involvement that those with normal complement levels.

Several clinical differences exist between idiopathic chronic urticaria and urticarial vasculitis. The duration of rash is shorter in idiopathic urticaria. The rash resolves in less than 24 hours (often 2 to 4 hours) and disappears while new plaques appear in other areas. In vasculitis, the rash persists for 24 to 72 hours. Residual changes are not seen in idiopathic urticaria while in vasculitis, purpura, scaling and/or hypopigmentation are seen. In idiopathic urticaria,

Table 1: Common Causes of Urticaria

the rash is itchy while the lesions in vasculitis are painful and burning.

Biopsy shows a characteristic histologic picture which is indistinguishable from that seen in cutaneous necrotizing vasculitis, also called palpable purpura or leukocytoclastic vasculitis because of the fragmentation of leukocytes and fibrinoid deposition occurring in the walls of post capillary venules. One has to rule out other diseases in which cutaneous vasculitis may present as an urticarial-like eruption, e.g. systemic lupus erythematosus, Sjorgen's syndrome, viral illnesses and serum sickness.¹⁷ Treatments with prednisone, indomethacin, colchicine, dapsone, and methotrexate have been reported to be effective.^18-20

Histamine is the most important chemical mediator. It is contained in the granules of mast cells. A variety of immunologic and non-immunologic physical and chemical stimuli react with different cell membrane receptors of mast cells. Activation of one group of receptors stimulates the conversion of ATP to cAMP which inhibits histamine release while activation of another group of receptors stimulates the conversion of GTP to cGMP which leads to histamine release.

Histamine, when injected into the skin or released into the tissues by degranulation of mast cells, produces the triple response. It starts with local erythema from vasodilation, followed by the flare characterized by erythema beyond the border of the local erythema and leads to a wheal produced from the leakage of fluid from the post capillary venule. Histamine, by causing contraction of the endothelial cells, allows vascular fluid to leak between the cells through the vessel wall contributing to tissue edema and wheal formation.

Histamine induces vascular changes by a number of mechanisms. Blood vessels contain at least two receptors for histamine designated as H₁ and H₂ receptors. Acting through the H₁ receptors, histamine causes an axon reflex vasodilation, pruritus, sneezing, and smooth muscle contraction in respiratory and gastrointestinal tracts. Acting through the H₂ receptors, it increases gastric acid secretion and vasodilation. Binding of histamine to the H₂ receptors on the surface of mast cells inhibits further production of histamine. Activation of both H₁ and H₂ receptors causes hypotension, tachycardia, flushing, and headaches.

General treatment measures of urticaria include avoidance of alcohol overuse, overtiredness, and overheated surroundings. Patients also need explanation about the course of the disease and reassurance. Frequent tepid showers and application of 1% menthol in aqueous cream can very helpful. Antihistamines are useful. Antihistamines have a similar chemical structure to histamine and compete for the same receptor sites. If histamine has been released before an antihistamine is taken, the receptor site will be occupied and the antihistamine will have little effect.

H₁ antagonists are useful for the management of chronic urticaria. Since they are structurally similar to atropine, they can produce atropine like peripheral and central cholinergic effects such as dry mouth, blurred vision, constipation, and dizziness. First generation antihistamine H₁ receptor antagonists such as hydroxyzine and diphenhydramine cross the blood brain barrier and produce sedation. However, there is marked individual variation in response and side effects. In children, stimulation rather than sedation can happen as well as focal seizures. Generally, the efficacy does not decrease with prolonged use. Tolerance to adverse CNS effects is variable. Some patients who do not respond to an initial first generation antihistamine may respond to another alternative first generation drug.

Combinations of agents may be more effective than a single agent. The combination of hydroxyzine and cyproheptadine is particularly useful. Although it would seem that the combination of H₁ and H₂ antihistamines would provide optimum effects, studies showed conflicting results and generally showed that the combination is no more effective than an H₁ blocking agent used alone. An exception is in refractory cases of dermographism in which the combination of chlorpheniramine (H₁) and cimetidine (H₂) proved more effective.²¹

Second generation antihistamines are non-sedating because they do not cross the blood brain barrier. They also have much longer half lives, but may have significant drug interactions.

Tricyclic antidepressants are potent blockers of H₁ and H₂ receptors. The most potent is doxepin. It is approximately 775 times more potent as an H₁ blocker than diphenhydramine and approximately 56 times more potent than hydroxyzine.²² As an H₂ blocker, doxepin is approximately 6 times more potent than cimetidine. Doxepin is a good alternative for patients who are not controlled with conventional antihistamines. With doxepin, lethargy, which is generally observed at the beginning of treatment, usually diminishes with continued use. Dry mouth and constipation are among the common side effects. Higher doses are better tolerated if taken in the evening.

Oral corticosteroids should be considered only for refractory cases. Other agents reported to have potential efficacy include methotrexate, acyclovir, and leukotriene receptor antagonists.^23-25