The New England Journal of Medicine

Clinical Practice
Volume 346:175-179

January 17, 2002

Number 3
Chronic Urticaria and Angioedema
Allen P. Kaplan, M.D.

This Journal feature begins with a case vignette highlighting a common
clinical problem. Evidence supporting various strategies is then presented,
followed by a review of formal guidelines, when they exist. The article ends
with the author's clinical recommendations.
A 35-year-old woman presents with a three-month history of daily generalized
hives. The hives are pruritic, red wheals that range from 1.5 to 8.0 cm (0.5
to 3 in.) in diameter. She has frequent episodes of lip swelling and has
also had three episodes of tongue swelling, one of which was associated with
tightness of the throat. How should she be evaluated and treated?
The Clinical Problem
The case vignette describes a typical patient with chronic urticaria (
Figure 1 <http://content.nejm.org/cgi/content/short/346/3/#F1> ) and
angioedema. The disorder is diagnosed when hives occur on a regular basis
for more than six weeks. This interval is sufficient to rule out most
identifiable causes of acute urticaria, such as drug reactions and food or
contact allergies. Angioedema accompanies urticaria in approximately 40
percent of patients and, when present, typically affects the lips, face
(particularly the periorbital area), hands, feet, penis, or scrotum.
Occasionally there may be swelling of the tongue or pharynx, but the larynx
is virtually never involved. Another 40 percent of patients have hives
alone, and about 20 percent of patients have angioedema but not urticaria.


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Figure 1. Typical Urticarial Lesions in a Patient with Chronic Urticaria.
The lesions are erythematous, roughly circular, and sometimes confluent,
with areas of central clearing.

Strategies and Evidence
Diagnosis
The most common alternative diagnosis is hives due to dermatographism (
Figure 2 <http://content.nejm.org/cgi/content/short/346/3/#F2> ); in severe
cases, patients will have hives every day for months or years. They are
commonly linear, but they can be any shape. In dermatographism, individual
hives last 30 minutes to 2 hours, as they do in most other types of
physically induced hives (e.g., cold urticaria, cholinergic urticaria, and
solar urticaria). In contrast, the hives associated with chronic urticaria
last 4 to 36 hours. 1 <http://content.nejm.org/cgi/content/short/346/3/#R1>
Patients with chronic urticaria may also have mild dermatographism, but the
hives associated with primary dermatographism are much more severe.


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Figure 2. Evidence of Dermatographism.
Scratching the skin leads to a linear wheal within two minutes in a patient
with dermatographism.

The patient's history and findings on physical examination may suggest an
underlying cause of urticaria. Occasionally, chronic urticaria and
angioedema are manifestations of an underlying connective-tissue disorder or
a systemic vasculitis in which the findings on histologic examination of the
underlying skin may be consistent with a leukocytoclastic angiitis rather
than the nonnecrotizing vasculopathy typical of chronic urticaria. However,
cutaneous vasculitis accounts for less than 1 percent of all cases of
chronic hives.
Hashimoto's disease is the only systemic disorder with a clear and common
association with chronic urticaria and angioedema. 2
<http://content.nejm.org/cgi/content/short/346/3/#R2> , 3
<http://content.nejm.org/cgi/content/short/346/3/#R3>  Less common is an
association with Graves' disease. The percentage of patients with chronic
urticaria who have antithyroglobulin antibody, antimicrosomal antibody, or
both is 27 percent, and 19 percent have abnormal thyroid function. 3
<http://content.nejm.org/cgi/content/short/346/3/#R3>  There is no evidence
to suggest that these antithyroid antibodies are pathogenic; the thyroid
abnormality appears to be a parallel abnormality and may reflect the
presence of an underlying autoimmune process.
Chronic urticaria appears to be an autoimmune disorder in a substantial
fraction of patients. Approximately 35 to 40 percent of patients have a
circulating IgG antibody directed against the {alpha}subunit of the IgE
receptor. 4 <http://content.nejm.org/cgi/content/short/346/3/#R4> , 5
<http://content.nejm.org/cgi/content/short/346/3/#R5> , 6
<http://content.nejm.org/cgi/content/short/346/3/#R6>  An additional 5 to 10
percent have antibodies against the {alpha}subunit of IgE. 7
<http://content.nejm.org/cgi/content/short/346/3/#R7>  These antibodies
activate basophils and mast cells to release histamine, and complement
fixation augments histamine release by formation of C5a anaphylatoxin. 8
<http://content.nejm.org/cgi/content/short/346/3/#R8>  The lesion is
characterized by a perivascular infiltration of lymphocytes that are
predominantly CD4-positive, an increased number of monocytes, and variable
numbers of neutrophils and eosinophils, 9
<http://content.nejm.org/cgi/content/short/346/3/#R9> , 10
<http://content.nejm.org/cgi/content/short/346/3/#R10>  similar to the
findings in a late-phase allergic reaction.
Chronic urticaria was once considered to be a manifestation of an anxiety
disorder or an allergic or idiosyncratic reaction to foods, food additives,
or food dyes. There are no good data to support these suppositions.
Adherence to a diet of rice, lamb, and water for five days has no effect on
chronic urticaria or angioedema. 1
<http://content.nejm.org/cgi/content/short/346/3/#R1>  Data to support or
refute an infectious cause of chronic urticaria, such as Helicobacter
pylori, are still being debated, but an infectious cause is unlikely. 11
<http://content.nejm.org/cgi/content/short/346/3/#R11>  An autoimmune
mechanism appears to be most likely, at least in a subpopulation of
patients, but 60 percent of cases remain idiopathic.
Evaluation
There are few, if any, diagnostic tests for chronic urticaria and
angioedema. The results of a complete blood count and urinalysis are
typically normal, as are the values for blood chemical variables usually
included in laboratory panels. If a connective-tissue disorder is suspected,
measurement of the erythrocyte sedimentation rate, tests for antinuclear
antibodies, and other serologic tests may be indicated, followed by a skin
biopsy. Complement determinations are not indicated for patients who have
hives alone (since the values are normal), nor need they be done when
angioedema accompanies chronic urticaria, since patients with a hereditary
or acquired deficiency of C1 inhibitor do not have hives. Only in patients
who present with angioedema alone is measurement of C4 indicated, followed
by a determination of the levels and function of C1 inhibitor, if C4 levels
are below normal. Thyroid-function tests, including tests for
antithyroglobulin and antimicrosomal antibodies, may be helpful, given the
association of chronic urticaria with thyroid disease, with an annual
reassessment of function in euthyroid patients who have elevated antibody
titers. Allergies (to food or food additives) are so rarely a cause of
chronic urticaria that routine testing is not recommended unless particular
clues are present. A skin biopsy may be helpful in patients who have fever,
arthralgias, a prominently elevated sedimentation rate, lesions lasting 36
hours or more, or associated petechiae or purpura.
Therapy
            Histamine H1–Receptor Antagonists
Nonsedating antihistamines such as loratadine, 12
<http://content.nejm.org/cgi/content/short/346/3/#R12>  fexofenadine, 13
<http://content.nejm.org/cgi/content/short/346/3/#R13> , 14
<http://content.nejm.org/cgi/content/short/346/3/#R14>  and cetirizine 15
<http://content.nejm.org/cgi/content/short/346/3/#R15> , 16
<http://content.nejm.org/cgi/content/short/346/3/#R16> , 17
<http://content.nejm.org/cgi/content/short/346/3/#R17> , 18
<http://content.nejm.org/cgi/content/short/346/3/#R18>  alleviate pruritus
and decrease the incidence of hives in patients with mild chronic urticaria.
Unfortunately, patients with more severe cases may not benefit from the
usual recommended doses of these agents. A study of 439 patients revealed
that fexofenadine, at a dose of 60, 120, or 240 mg per day, was
significantly more efficacious than placebo, as assessed by the mean
pruritus score, the mean number of wheals per day, the mean daily symptom
score (the sum of the wheal and pruritus scores), and the degree of
interference with sleep, activities of daily living, or both. 14
<http://content.nejm.org/cgi/content/short/346/3/#R14>  Increasing the dose
from 120 to 240 mg per day increased the efficacy only slightly 13
<http://content.nejm.org/cgi/content/short/346/3/#R13>  and larger doses did
not yield proportionate increases in efficacy.
A 10-mg dose of cetirizine, one of the active ingredients of hydroxyzine, is
approximately equivalent to a 30-mg dose of hydroxyzine but is far less
sedating. 17 <http://content.nejm.org/cgi/content/short/346/3/#R17>  In a
placebo-controlled study of cetirizine and hydroxyzine, 180 patients were
assessed with respect to the severity of pruritus, the number of lesions,
the average size and duration of lesions, and the number of episodes of
hives. 18 <http://content.nejm.org/cgi/content/short/346/3/#R18>  Both
agents produced similar improvements in every measured variable. 18
<http://content.nejm.org/cgi/content/short/346/3/#R18>  Only four patients
given hydroxyzine and one patient given cetirizine withdrew from the study
because of sedation. A potent new nonsedating antihistamine, mizolastine,
which is available in Europe but not in the United States, appears to be
efficacious for chronic urticaria.
High doses of antihistamines have effects beyond the blockade of histamine
receptors, and actions that are not due to the antagonism of H1 receptors 19
<http://content.nejm.org/cgi/content/short/346/3/#R19>  may account for the
efficacy of older antihistamines. In one study of 19 patients, treatment
with a combination of H1-receptor antagonists 20
<http://content.nejm.org/cgi/content/short/346/3/#R20>  (25 mg of
hydroxyzine plus 4 mg of cyproheptadine, each given four times a day) led to
an improvement in symptoms and inhibited the formation of histamine-induced
wheals. When hydroxyzine (100 mg per day) was compared with terfenadine (the
precursor of fexofenadine, now off the market), hydroxyzine was more
effective. 21 <http://content.nejm.org/cgi/content/short/346/3/#R21>
            Combined H1- and H2-Receptor Antagonists
Approximately 85 percent of histamine receptors in the skin are of the H1
subtype, and the remaining 15 percent are H2 receptors. The addition of an
H2-receptor antagonist to an H1-receptor antagonist augments the inhibition
of a histamine-induced wheal-and-flare reaction once H1-receptor blockade
has been maximized. On the basis of this rationale, H2-receptor antagonists
have been combined with H1-receptor antagonists in the treatment of chronic
urticaria, with additional benefit, 20
<http://content.nejm.org/cgi/content/short/346/3/#R20>  although the
increment is small. Doxepin, a tricyclic antidepressant, blocks both types
of histamine receptors and is a much more potent inhibitor of H1 receptors
than either diphenhydramine or hydroxyzine; however, sedation is an even
greater problem and may limit the usefulness of this drug. 22
<http://content.nejm.org/cgi/content/short/346/3/#R22>
            Leukotriene Antagonists
Leukotriene antagonists (zafirlukast and montelukast) have been shown to be
superior to placebo in the treatment of patients with chronic urticaria, 23
<http://content.nejm.org/cgi/content/short/346/3/#R23> , 24
<http://content.nejm.org/cgi/content/short/346/3/#R24>  indicating that
leukotrienes may also contribute to hives and swelling. There are no data to
support the hypothesis that these agents have an additional effect once
maximal H1- and H2-receptor blockade has been achieved.
            Sympathomimetic Agents
Oral sympathomimetic agents such as terbutaline have been tried in patients
with chronic urticaria and angioedema in an attempt to decrease erythema and
swelling. However, since the side effects are substantial and include
difficulty sleeping, a jittery feeling, and tachycardia — and since the
efficacy of these agents is low — they are not generally recommended.
            Corticosteroids
There are many patients with chronic urticaria and angioedema who have
little response to even a combination of H1-receptor blockers, H2-receptor
blockers, and leukotriene-receptor blockade and in whom disability due to
the disease warrants consideration of corticosteroid therapy. Although
controlled studies of the long-term use of corticosteroids have not been
conducted, there is truly no question regarding their efficacy. 1
<http://content.nejm.org/cgi/content/short/346/3/#R1>  However, the
incidence of side effects is substantial if the dose, the duration of use,
or both are too great; in addition, their use may trigger diabetes or
hypertension in patients at increased risk for these diseases.
            Experimental Therapies
The best studied immunosuppressive therapy for chronic urticaria is
cyclosporine, although studies have been uncontrolled and have involved only
a small number of patients. A low dose (2.5 to 3 mg per kilogram of body
weight per day) appeared to be effective and corticosteroid sparing, 25
<http://content.nejm.org/cgi/content/short/346/3/#R25>  whereas a larger
dose (6 mg per kilogram) was quite effective but was associated with severe
side effects that precluded its continued use. 26
<http://content.nejm.org/cgi/content/short/346/3/#R26>
A single case report indicated that sulfasalazine was effective for chronic
urticaria, and case reports have suggested that hydroxychloroquine or
dapsone might also be effective, but blinded studies involving a large
number of patients have not been conducted. Plasmapheresis has been
advocated for the subgroup of patients with demonstrable antibodies against
the IgE receptor, 27 <http://content.nejm.org/cgi/content/short/346/3/#R27>
but this approach is impractical for long-term treatment. Intravenous immune
globulin was effective in one small study, 28
<http://content.nejm.org/cgi/content/short/346/3/#R28>  but this report has
not been confirmed. Treatment with levothyroxine has been proposed in
patients with antithyroid antibodies, even if the patient is euthyroid. 29
<http://content.nejm.org/cgi/content/short/346/3/#R29>  Such treatment,
however, carries a risk of inducing hyperthyroidism, and its efficacy has
not been proved. 3 <http://content.nejm.org/cgi/content/short/346/3/#R3>
Areas of Uncertainty
We need to document whether high doses of antihistamines, particularly the
nonsedating types, are superior to lower doses. Leukotriene-receptor
antagonists need to be evaluated in combination with antihistamine regimens,
rather than in placebo-controlled trials. Long-term studies of
corticosteroids are needed to clarify the dose range that yields the maximal
benefit with the fewest side effects, and to compare the effect of these
agents when they are used alone and when they are added to other regimens.
Further studies of experimental agents such as cyclosporine or perhaps
tacrolimus are needed to assess their safety and efficacy as
corticosteroid-sparing agents.
Guidelines
A "practice parameter" for the diagnosis and management of acute and chronic
urticaria was published in 2000 30
<http://content.nejm.org/cgi/content/short/346/3/#R30> ; it emphasizes the
conditions that need to be considered in the differential diagnosis, such as
urticarial vasculitis, connective-tissue disorders, systemic mastocytosis,
and idiopathic anaphylaxis.
Summary and Recommendations
In a patient with chronic urticaria who has no signs or symptoms suggestive
of an underlying condition, laboratory testing is not indicated, other than
measurement of serum thyrotropin levels and antithyroid antibodies to rule
out associated thyroid disease. These are the only tests I would recommend
for the patient described in the vignette. Although there is no single right
way to manage chronic urticaria and angioedema, there is general agreement
that nonsedating antihistamines are the first choice for treatment. When
severe urticaria, severe angioedema, or both are present, I believe that the
older antihistamines are more effective than the newer ones, when maximal
doses of these agents are given (e.g., 100 to 200 mg of hydroxyzine or
diphenhydramine per day) ( Table 1
<http://content.nejm.org/cgi/content/short/346/3/#T1> ). For patients with
severe angioedema (involving swelling of the face, tongue, and pharynx),
diphenhydramine is particularly effective.


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Table 1. Medications Used to Treat Chronic Urticaria and Angioedema.

Although patients become accustomed to the sedating effects of these drugs
after about a week, their performance on various tests, such as driving,
after a single 50-mg capsule of diphenhydramine 31
<http://content.nejm.org/cgi/content/short/346/3/#R31>  reflects a decreased
reaction time and decreased steadiness; these effects are similar to the
effects produced by alcohol. Yet the effect of long-term treatment with
hydroxyzine or diphenhydramine at a dosage of 50 mg four times a day has not
been assessed. H2-receptor antagonists have very few side effects and may be
useful as adjunctive therapy. Leukotriene antagonists are also considered
safe and are worth trying. The goal is to maximize function (e.g., the
patient's ability to work or attend school) and minimize the use of systemic
corticosteroids.
There is an important role for alternate-day corticosteroid use in patients
with severe disease. One approach has been outlined in a number of
textbooks, 1 <http://content.nejm.org/cgi/content/short/346/3/#R1>  although
it has not been evaluated in clinical trials. Prednisone is started at a
dose of 15 to 20 mg every other day, and the dose is gradually tapered to
2.5 to 5.0 mg every three weeks, depending on the patient's response, and
discontinued after four to five months. Side effects are minimized with the
use of dietary discretion and exercise. Chronic urticaria improves with
time, and the condition of many patients can then be controlled without
corticosteroids.
The patient described in the vignette may require not only the maximal
dosage of an H1-receptor antagonist (e.g., 50 mg of hydroxyzine four times a
day), plus an H2-receptor antagonist and a leukotriene antagonist, but also
alternate-day corticosteroids if a satisfactory response is not achieved.
Occasional episodes of severe facial or pharyngeal swelling can be treated
with one or two doses of a corticosteroid, such as 40 to 60 mg of prednisone
( Table 1 <http://content.nejm.org/cgi/content/short/346/3/#T1> ).
Patients who require alternate-day corticosteroids for more than six months
should be examined annually by an ophthalmologist (for cataracts and
glaucoma) and should undergo bone-density testing annually. In my practice,
daily corticosteroids are never used, and the dose of alternate-day
corticosteroids rarely exceeds 20 mg ( Table 1
<http://content.nejm.org/cgi/content/short/346/3/#T1> ). Some patients have
no responses to any of these approaches, or have a response only to
prohibitively high doses of corticosteroids. Of the experimental options,
200 to 300 mg of cyclosporine per day appears to be the best, as long as
renal function is closely monitored.

Source Information
From the Department of Medicine, Division of Pulmonary and Critical Care
Medicine and Allergy and Clinical Immunology, and Konishi–Medical University
of South Carolina Institute for Inflammation Research, Medical University of
South Carolina, Charleston.
Address reprint requests to Dr. Kaplan at Medical University of South
Carolina, Division of Pulmonary and Critical Care Medicine, Allergy and
Clinical Immunology, 96 Johnathan Lucas St., Suite 812 CSD, P.O. Box 250623,
Charleston, SC 29425, or at [log in to unmask] <mailto:[log in to unmask]> .
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.