American Journal of Clinical Dermatology
Urticaria - A Review
Tasneem Poonawalla; Brent Kelly
Posted: 05/08/2009; Am J Clin Dermatol. 2009;10(1):9-21. © 2009 Adis Data Information BV
Abstract and Introduction
Abstract
Urticaria is often classified as acute, chronic, or physical based on duration of symptoms and the presence
or absence of inducing stimuli. Urticarial vasculitis, contact urticaria, and special syndromes are also
included under the broad heading of urticaria. Recent advances in our understanding of the pathogenesis
of chronic urticaria include the finding of autoantibodies to mast cell receptors in nearly half of patients
with chronic idiopathic urticaria. These patients may have more severe disease and require more
aggressive therapies. Extensive laboratory evaluation for patients with chronic urticaria is typically
unrevealing and there are no compelling data that associate urticaria with chronic infections or
malignancy. Pharmacologic therapy consists primarily of the appropriate use of first- and secondgeneration histamine H1 receptor antihistamines. Additional therapy may include leukotriene receptor
antagonists, corticosteroids, and immunomodulatory agents for severe, unremitting disease. Despite our
greater understanding of the pathogenesis of urticaria, the condition remains a frustrating entity for many
patients, particularly those with chronic urticaria.
Introduction
Urticaria, commonly called 'hives,' has a long and rich history in documented medicine dating back at
least to the 10th century B.C. when it was called 'Feng Yin Zheng' in China.[1] Many cultures have
described urticaria in some capacity and the disorder has had many names. In the 4th century B.C.,
Hippocrates noted the similarities between urticaria, contact with stinging nettles, and insect bites and
called the condition 'cnidosis' (nettle rash).[2] 'Uredo,' 'essera' (Arabic for elevation), 'urticatio' (derived
from the Latin urere; to burn), and 'scarlatina urticaria' have all been used.[2] Use of the term 'morbus
porcinus', which means pig's disease, resulted from a translational error of the intended term 'morbus
pocellaneus,' which referred to the white color of the central wheal.[3] William Cullen was probably the
first to use the term urticaria in 1769.
Nearly as many theories about the pathogenesis of urticaria have been described including, among others,
a humoral theory (relating urticaria to body 'humors'), a metereologic theory in 1823 (suggesting that
allergy was determined by the constellation of the stars), and a menstrual theory in 1864 (proposing that
urticaria was related to endogenous hormones).[1] It was the discovery of the mast cell in 1879 by Paul
Ehrlich that led to our current understanding of allergy pathogenesis, including urticaria. However, despite
improvements in our understanding of urticaria, the condition remains a frustrating disorder for many
patients, particularly those with chronic urticaria. This review attempts to classify urticaria and discuss the
evidence-based pathogenesis and treatment options available, with particular emphasis on chronic
urticaria.
1
A MEDLINE search using Ovid was performed to obtain the articles reviewed. Search terms included
'urticaria' and 'hives' and were applied from 1950 to the date of review. Relevant articles, particularly
those relating to history, pathogenesis, and treatment, were included in this review. Articles were excluded
if they did not add to the known knowledge base of the subject. Additional relevant articles were obtained
from citations in the reference sections of identified articles.
Clinical Features and Epidemiology
Urticaria consists of recurrent wheals that are usually pruritic, pink-to-red edematous plaques that often
have pale centers. The wheals are transient, and in most types of urticaria last for <24 hours.[4] The wheals
range in size from a few millimeters to several centimeters in diameter. They can, however, become
confluent and form plaques. Urticarial wheals are generally paler than the erythematous surrounding skin
because of the compressing effect of dermal edema on post-capillary venules. Wheals may be round or
irregular and may occur anywhere on the skin, including the scalp, palms, and soles. They are quite
pruritic with maximal intensity in the evenings and night-time and occasionally may be 'burning' or
'pricking' in quality. This itch is unique in that it is relieved more so by rubbing than by scratching, and
purpura rather than excoriations are a more common consequence of urticaria.[5]
Urticaria is a worldwide disease and may present at any age. The lifetime occurrence of urticaria in the
general population ranges from 1% to 5%.[6,7]
Classification
Classification of urticaria is most often based upon clinical characteristics rather than etiology (see Table
I). Unfortunately, it is often difficult to determine the etiology or pathogenesis of individual cases of
urticaria and many cases remain idiopathic. Six weeks of daily or nearly daily symptoms is a somewhat
arbitrary, but nonetheless useful, time period for separating acute from chronic urticaria. Angioedema can,
and often does, accompany the urticarial lesions. Angioedema without urticaria, however, should raise
suspicion of an acquired or hereditary form (particularly complement [C]-1-inhibitor deficiency), which
can often be more severe with laryngeal involvement. Other categories of urticaria include contact
urticaria, urticarial vasculitis, and physical urticaria. Physical urticaria, a unique and often debilitating
form of the disorder, results from a specific trigger. Subtypes include aquagenic, cholinergic, cold,
delayed pressure, dermatographism-related, localized heat, and solar and vibratory urticaria.[4,5]
2
Table I. Classification of Urticaria
Ordinary urticarias
Acute urticaria
Chronic urticaria
Contact urticaria
Physical urticarias
Dermatographism
Immediate
Delayed
Cholinergic urticaria
Vibratory angioedema
Exercise-induced urticaria
Adrenergic urticaria
Delayed-pressure urticaria
Solar urticaria
Aquagenic urticaria
Cold urticaria
Special syndromes
Schnitzler syndrome
Muckle-Wells syndrome
Pruritic urticarial papules and plaques of pregnancy
Urticarial bullous pemphigoid
Urticarial vasculitis
Acute Urticaria
Acute urticaria, by definition, is wheals occurring for <6 weeks. The individual lesions typically resolve in
<24 hours, occur more commonly in the pediatric population,[4] and are often associated with atopy.
Between 20% and 30% of patients with acute urticaria progress to chronic or recurrent urticaria.[8]
Etiologic data suggest that acute urticaria is idiopathic in about 50% of patients, due to upper respiratory
tract infections in 40%, to drugs in 9%, and to foods in 1%.[4] Food allergies probably contribute more
often than is reflected in these data, but are under-represented because patients often self-diagnose and
then avoid the offending agent. Acute urticaria precipitated by foods, drugs (most notably, ß-lactam
antibacterials), insects, contact with an external agent, or parasites is often IgE dependent. Opioids,
muscle relaxants, radiocontrast agents, and vancomycin often cause urticaria via direct mast cell
degranulation and proinflammatory mediator release. Complement-mediated acute urticaria can be
triggered by serum sickness, transfusion reactions, and viral or bacterial infections. Finally, acetylsalicylic
acid (aspirin) and NSAIDs can cause acute urticaria through their effects on the metabolism of
arachidonic acid.[4]
3
Chronic Urticaria
Chronic urticaria is defined as the development of cutaneous wheals that occur on a regular basis (usually
daily) for >6 weeks with individual lesions lasting from 4 to 36 hours. The symptoms can be severe and
can impair health-related quality of life.[9] Detailed epidemiologic studies are not available and published
studies are problematic in that some include the physical urticarias and urticarial vasculitis while others do
not. Additionally, establishing cause and effect is difficult and many cases remain idiopathic. By some
estimates, the physical urticarias account for approximately 35% of all cases of chronic urticaria, while
urticarial vasculitis makes up about 5%.[4] A small percentage of chronic urticaria is caused by an
infection or pseudoallergy. Although many cases of chronic urticaria remain classified as idiopathic,
recent evidence suggests that a significant portion of the so-called idiopathic urticarias may have an
autoimmune etiology.[4,5] In general, chronic urticaria is more prevalent in female patients, occurring at a
2???1 female-to-male ratio.[4]
Contact Urticaria
Contact urticaria is defined as the development of urticarial wheals at the site where an external agent
makes contact with skin or mucosa. Contact urticarias can be subdivided into allergic (involving IgE) or
non-allergic (IgE-independent) forms. IgE-mediated allergic contact urticaria occurs in persons sensitized
to environment allergens such as grass, animals, or foods or to occupational allergens such as latex gloves
in healthcare workers. Non-allergic contact urticaria occurs as a result of the direct effects of urticants on
blood vessels. Examples of common urticants are sorbic acid in eye solutions, cinnamic aldehyde in
cosmetics, and chemicals from the stinging nettle (Urtica dioica), which include histamine, acetylcholine,
and serotonin.[4]
Physical Urticaria
Of the various urticarial disorders, the physical urticarias may affect quality of life most severely. [4] The
lesions of the physical urticarias are typically localized to the stimulated area and resolve within 2 hours
with the exception of delayed pressure and delayed dermatographism.[10] If a patient has a history of
wheals lasting for <1 hour, the presence of a physical urticaria should be considered. [4,5] Symptomatic
dermatographism – the most common form of physical urticaria – is not associated with systemic disease,
atopy, food allergy, or autoimmunity.[4] Conversely, patients with delayed-pressure urticaria may present
with systemic symptoms such as malaise, influenza-like symptoms, and arthralgias. Delayed-pressure
urticaria is distinguished by the development of deep erythematous swellings at sites of sustained pressure
to the skin after a delay of 30 minutes to as long as 12 hours. Examples of sites typically affected include
the waistline after the wearing of tight clothing and the area of the legs that makes contact with the elastic
band of socks. Many patients with delayed-pressure urticaria also have concurrent chronic idiopathic
urticaria.[5] Cholinergic urticaria – the second most common type of physical urticaria – is characterized
by a wheal surrounded by an obvious flare in response to physical exertion, hot baths, or sudden
emotional stress.[4] Adrenergic urticaria, in contrast to cholinergic urticaria, is characterized by blanched,
vasoconstricted skin surrounding small pink wheals. Other categories of physical urticaria include cold
urticaria, solar urticaria, aquagenic urticaria, pressure urticaria, and vibrating angioedema.
Challenge testing to confirm the diagnosis of a physical urticaria can be performed in the office setting.
Cholinergic urticaria can be diagnosed with exercise or hot bath testing. The lesions of cold urticaria can
be induced with the ice cube test. Aquagenic urticaria can be confirmed with application of water
compresses. Testing for pressure urticaria can be performed by applying an 8-kg weight to the patient's
thigh.[4]
4
Special Syndromes
Schnitzler syndrome is a unique variant of chronic urticaria characterized by recurrent non-pruritic
wheals, intermittent fever, bone pain, arthralgias or arthritis, an elevated erythrocyte sedimentation rate
(ESR), and a monoclonal IgM gammopathy. IgM may play an important role in wheal formation as it has
been demonstrated around dermal vessels and IgM autoantibodies directed against skin have been
reported.[11] Some investigators believe that Schnitzler syndrome may be a variant of urticarial vasculitis
rather than chronic urticaria. Interestingly, Saurat et al.[12] found that patients with Schnitzler syndrome
had IgG antibodies directed against the cytokine interleukin (IL)-1. Biopsies of lesions from patients with
clinical features of Schnitzler syndrome often demonstrate an increased polymorphonucleocyte count with
occasional leukocytoclasia.[13]
Muckle-Wells syndrome, an autoinflammatory disorder associated with cold-induced autoinflammatory
syndrome-1 gene mutations, is a rare entity characterized by urticaria, arthralgias, progressive
sensorineural deafness, and amyloidosis. Familial cold autoinflammatory syndrome is a similar entity that
seems to be related to changes in temperature.[14]
Pruritic urticarial papules and plaques of pregnancy (PUPPP), also known as polymorphic eruption of
pregnancy, is the most common dermatosis associated with pregnancy. Its lesions are often urticarial and
involve the trunk, particularly abdominal striae. PUPPP typically runs a benign, self-resolving course with
an onset in the third trimester. It is important to differentiate this disorder from the more serious
pemphigoid gestationis, a bullous pemphigoid like-disorder associated with pregnancy.[15]
Urticarial Vasculitis
The clinical presentation of urticarial vasculitis may be indistinguishable from that of chronic urticaria.
Nonetheless, the characteristics of the wheals may be helpful in differentiating urticarial vasculitis from
chronic urticaria. In contrast to chronic urticaria, the lesions of urticarial vasculitis tend to last longer than
24 hours and are associated with burning and pain in addition to itching. These lesions are also described
as healing with purpura or petechiae; however, the most common cause of purpura after urticaria is
probably scratching.[4,16] In patients with suspected urticarial vasculitis, histologic examination of a skin
biopsy specimen typically shows evidence of leukocytoclastic vasculitis. Urticarial vasculitis is rare, with
reported ranges of 1–10% in patients with chronic urticaria.[4,16] The incidence is probably closest to 1% in
most experts' opinion. When it does occur, urticarial vasculitis is typically a component of a chronic
systemic illness such as systemic lupus erythematosus, hypocomplementemic urticarial vasculitis
syndrome, Sjögren syndrome, or mixed cryoglobulinemia.[17]
Etiology
Unfortunately, most cases of chronic urticaria remain idiopathic. Recent data suggest that 35–50% of
chronic urticaria cases are related to autoimmunity, specifically the presence of autoantibodies to the highaffinity IgE constant fragment receptor-1 (FceR1) located on mast cells.[18] This results in chronic
stimulation of these mast cells and release of vasoactive mediators. Although not widely used, an in vivo
test known as the autologous serum skin test (ASST) can separate these patients from the remaining
idiopathic cases. The ASST is a modified skin allergy test using the patient's own serum injected
intradermally to elicit wheal formation.[18,19] This test and the importance of autoimmune chronic urticaria
are discussed further in section 5.
In addition to autoimmune causes, other identifiable causes of chronic urticaria include IgE-dependent,
complement-mediated, or immune complex deposition. Non-immunologic causes may include direct mast
5
cell release, vasoactive stimuli, alterations in prostaglandin (PG) pathways as a result of intake of
acetylsalicylic acid and other NSAIDs, dietary pseudoallergens (rarely), and alterations in the bradykinin
pathway as a result of use of ACE inhibitors.[4,18,20]
Food allergy and food additives such as preservatives and coloring agents do not appear to be significant
causes of chronic urticaria.[19] It is possible that impaired gastroduodenal barrier function may be of
pathophysiologic importance in the development of pseudoallergic reactions, and despite the rare
association of chronic urticaria with food allergies, some clinicians recommend that patients try an
elimination diet at least once in their lifetime.[13,21] Most, however, feel that this approach is unnecessary
and that food allergy can be ruled out as a cause by the history. Food allergies typically would cause a
reaction within 30 minutes of ingestion.[22]
Both Hashimoto thyroiditis and Graves disease have been associated with chronic urticaria. Antithyroid
antibodies, antimicrosomal antibodies, or both have been found in up to 27% of patients with chronic
urticaria.[23,24] A recent study showed that patients with chronic urticaria who had a positive ASST result
had significantly more autoimmune thyroid disease and abnormal thyroid function with abnormal thyroid
microsomal antibodies and abnormal thyroid-stimulating hormone than ASST-negative patients.[25] Also,
other investigators have found that patients with chronic autoimmune urticaria have significantly more
antithyroid peroxidase antibody than patients with chronic idiopathic urticaria (p = 0.03).[26] About 19% of
patients with chronic urticaria have abnormal thyroid function.[27] However, there is no evidence that the
antibodies involved in thyroid disorders play a role in the pathogenesis of chronic urticaria; this
association most likely represents parallel but unrelated autoimmune events.[19] Additionally, there is only
anecdotal evidence that both refutes and supports treatment of urticaria with levothyroxine sodium in
euthyroid patients. In patients with both chronic urticaria and autoimmune thyroiditis, the ASST can
continue to be positive after remission of urticaria. This suggests that some component of thyroid disease
can enhance a positive ASST. Almost all patients with autoimmune thyroiditis and no history of urticaria
have a negative ASST,[28] which correlates ASST more with chronic urticaria than with thyroiditis. This
phenomenon needs further study to verify the reliability of a positive ASST as a surrogate marker of
circulating anti-FceRI and anti-IgE autoantibodies in patients with coexisting chronic urticaria and
autoimmune thyroiditis.[28] Other autoimmune conditions associated with chronic urticaria include vitiligo,
insulin-dependent diabetes mellitus, rheumatoid arthritis, and pernicious anemia.[29,30]
It has been proposed that Helicobacter pylori, which has an immunogenic cell envelope, may play an
indirect role in the etiology of chronic autoimmune urticaria by reducing immune tolerance and inducing
autoantibody formation, such as anti-FceRI.[19,26] Some investigators have found an increased frequency of
H. pylori IgG antibodies in patients with chronic urticaria,[31] while others have not.[32] Whether
eradication of H. pylori is effective in the treatment of chronic urticaria is a controversial issue, and the
limited number of studies of this question have yielded conflicting results.[31] In a systematic review of
published studies of the effects of H. pylori eradication on the rate of remission of chronic urticaria,
Federman et al.,[33] in 2003, found that urticaria was more likely to resolve when antibacterial therapy
successfully eradicated H. pylori than when eradication was unsuccessful. Since then, data have both
refuted and confirmed improvements in urticaria with successful eradication of H. pylori.[34-36] Although
many experts are not convinced of a causative role of H. pylori in chronic urticaria, an evaluation for its
presence may still be considered, particularly since H. pylori infection is also associated with mucosaassociated lymphoid tissue lymphoma and gastric adenocarcinoma and an effective treatment is available.
There is no association between chronic urticaria and malignancy.[37,38] Although an association between
urticaria and occult infections such as dental abscesses or gastrointestinal candidiasis has been proposed,
there is little supporting evidence other than anecdotal reports.[38] A few case reports have described
resolution of recalcitrant chronic urticaria after treatment of dental abscesses.[39] Parasitic infections such
6
as intestinal strongyloidiasis may occasionally cause chronic urticaria in endemic areas.[37] The fish
nematode Anisakis simplex has been implicated as a cause of chronic urticaria based on detection of IgG4
antibodies.[40,41] Although a study[42] from Japan suggested a possible link between hepatitis C and chronic
urticaria, other investigations, including a large prospective study[43] conducted in France, have found no
association between the hepatitis C virus and urticaria.[37] No conclusive evidence is available linking
chronic urticaria with hepatitis B, Epstein-Barr virus, cytomegalovirus, or HIV.[39]
There is some evidence that genetic factors play a role in the pathogenesis of chronic urticaria. In a study
of more than 1300 patients with chronic idiopathic urticaria, Asero[44] found that the prevalence of the
disease was much higher among first-degree relatives of the study group than in the general population.
O'Donnell et al.[45] have shown that, compared with control individuals, patients with chronic idiopathic
urticaria have an increased frequency of HLA-DR4 and HLA-D8Q. HLA-DR4 is strongly associated with
autoimmune chronic urticaria.
Pathogenesis
The mast cell is the principal effector cell of urticaria. Mast cells are distributed throughout the body but
vary in their response to stimuli. All mast cells express high-affinity IgE receptors (FceRIs) that enable
their involvement in IgE-dependent allergic reactions. The constant region domain of IgE, Ce3, is the
major site of interaction with the IgE receptor. When IgE forms a complex with FceRI on the mast cell to
which an allergen binds, degranulation occurs.[20] Mast cell degranulation also occurs through a variety of
other mechanisms, including cross-linking of adjacent FceRI, binding of receptor-bound IgE by allergen,
anti-IgE, and anti-FceRI antibodies. Non-immunologic stimuli such as opioids, C5a anaphylotoxin, and
stem cell factor as well as neuropeptides such as substance P can cause degranulation via direct
stimulation. These stimuli initiate calcium- and energy-dependent steps that cause storage granules to fuse
with the cell membrane and externalize their contents, which include preformed and newly synthesized
mediators of inflammation. FceRI stimulation also leads to upregulation of the synthesis and secretion of
proinflammatory mediators.[4,19,20]
The key mediator is histamine. Preformed cytokines, including tumor necrosis factor (TNF)-a, IL-3, IL-4,
IL-5, IL-6, IL-8, IL-13, and granulocyte-macrophage colony-stimulating factor (GM-CSF), are also
released. Newly synthesized mediators from arachidonic acid include PGD2 and leukotrienes C4, D4, and
E4.[4,19,20] Leukotriene C4 is 1000 times more potent than histamine in causing a wheal-and-flare reaction
and thus can also be considered an additional mediator of urticaria.[46] Histamine, TNFa, and IL-8
upregulate the expression of adhesion molecules on endothelial cells and encourage migration of
circulating inflammatory cells from the blood into the urticarial lesion.[4] IL-4 promotes further IgE
production that causes positive feedback. One study has shown that the serologic immune profile of
patients with chronic autoimmune urticaria is a mixed T helper-1 (Th1)/Th2 pattern with a slight Th2
predominance due to increased IL-13 production.[47] IL-13 shares biologic properties with IL-4 and may
increase mast-cell FceRI expression and mediator release. Another study found evidence for a prevalent
role of lymphocytes with a mixed Th1/Th2 response focally expressing interferon-? and IL-5 in autologous
wheals.[48] The investigators also reported that the main infiltrating population was neutrophils with
involvement of the chemokine pathway. Additionally, they found that uninvolved skin in persons with
chronic idiopathic urticaria had latent inflammation with a lymphocytic and granulocytic cellular infiltrate
with mediator upregulation, which may represent a prolonged and widespread urticarial state.[48]
Histology of chronic urticaria (both idiopathic and autoimmune) demonstrates a perivascular nonnecrotizing infiltrate of CD4+ lymphocytes consisting of a mixture of Th1 and Th2 subtypes, plus
monocytes, neutrophils, eosinophils, and basophils.[49] Other observations include increased levels of
matrix metalloproteinase-9 in patients afflicted with chronic urticaria, especially those with severe disease.
7
In addition, there is evidence that CD4+ T cells are highly activated, with increased nuclear factor-?B
(NF-?B) expression leading to increased B-cell lymphoma (bcl)-2 expression in the T cells of patients
with chronic urticaria.[50] Substance P does not appear to play a noteworthy role in chronic urticaria,
although it may occasionally function as an alternate mode of triggering urticaria.[51]
Initial evidence of autoimmune involvement in chronic urticaria was reported by Hide et al. [18] who
showed autoantibodies of the IgG subclass against FceRI on mast cells and basophils. Only patients with
chronic urticaria have been shown to manifest functional histamine-releasing anti-FceRI autoantibodies.
These antibodies do not occur in physical urticarias, atopic eczema, or other diseases involving activated
mast cells.[5] About 35–40% of patients with chronic urticaria have IgG antibodies to the a subunit of the
FceRI, and 5–10% have IgG antibodies to IgE itself. Those autoantibodies that recognize the a2 domain
on the FceRI compete with IgE for the binding site, whereas non-competitive autoantibodies are directed
against the a1 domain and are able to bind even in the presence of IgE.[4,19]
Autoantibodies to mast cells may also initiate complement activation with generation of C5a
anaphylatoxin leading to degranulation.[52] The antibodies involved are primarily IgG1 and IgG3, which
are often considered to be involved in complement activation. IgG4 is also occasionally involved,
although, unlike IgG1 and IgG3, it is not complement fixing.[53] It is interesting to note that only IgG in
sera with complement will release histamine from dermal mast cells, which indicates that the release of
histamine from dermal mast cells by FceRI is most likely augmented by complement activation. This
finding is further supported by the fact that patients with severe autoimmune chronic urticaria do not
experience bronchospasm because lung mast cells, unlike dermal mast cells, are devoid of complement
receptors. One study, however, did show that patients with chronic urticaria had bronchial hyperresponsiveness to methacholine provocation on pulmonary function tests.[54] This hyper-responsiveness
was not as severe as that observed in the asthmatic control patients.
In addition to autoantibodies, it is possible that other factors in sera or plasma may also contribute to mast
cell degranulation and urticaria formation. For example, some have suggested that only half of patients
with a positive ASST are able to induce histamine release from basophils in vitro.[55] Additionally, IgGdepleted sera were still able to maintain a wheal and flare. Some have suggested that components of the
coagulation cascade, particularly thrombin, may play a role.[56] Thrombin has been shown to increase
vascular permeability,[57] trigger mast cell degranulation and, indeed, may be equipotent to FceR1mediated activation. Autologous plasma skin tests (which would still include clotting factors) are more
frequently positive than ASST in patients with chronic urticaria, and serum levels of thrombin have been
directly related to urticaria severity.[58]
Diagnosis and Work-up
Studies have shown that taking a detailed patient history is usually adequate to establish a diagnosis of
chronic urticaria.[4,38,59-61] If laboratory tests are warranted, based on the history, an ESR and white blood
cell count with differential should be considered. Although the ASST is helpful in distinguishing some
cases of chronic autoimmune urticaria from chronic idiopathic urticaria,[4,38] this test is currently not
widely used. If a cause for the urticaria is not found, some clinicians recommend screening for H. pylori
infection. Thyroid function tests and tests for thyroid antibodies are necessary only when clinical findings
suggest the presence of thyroid disease.[37] Challenge testing is indicated when a patient is being evaluated
for a physical urticaria. Patients suspected of having urticarial vasculitis should undergo a skin biopsy to
confirm the diagnosis. Patients with angioedema but without urticaria should have C4 levels measured to
screen for C1-inhibitor deficiency; C1-inhibitor levels can be measured if the C4 level is low.[4,37,38]
8
Distinguishing between autoimmune chronic urticaria and idiopathic chronic urticaria is clinically
important because patients afflicted with the autoimmune form typically have a more aggressive disease
course and are more resistant to treatment. Sabroe et al.[29] have shown that patients with autoantibodies
have more wheals with a wider distribution, higher itch scores, more systemic symptoms, and lower serum
IgE levels than patients without autoantibodies. In addition, they are more likely to require and benefit
from immunosuppressive therapy. Establishing a diagnosis of autoimmune chronic urticaria is a difficult
task because there are no reliable laboratory tests to aid the clinician. A decrease in basophils (basopenia)
is a common feature of chronic urticaria and may be useful for screening for the autoimmune form of the
disease.[62,63] However, there are no convenient and reproducible methods of counting basophils in the
peripheral circulation. Unfortunately, no reliable direct antibody test is available and results with ELISA
and immunobinding techniques have been disappointing.[5]
Currently the most useful test for evaluating chronic urticaria is the ASST. A sample of the patient's own
serum (collected during a flare) is injected intradermally into uninvolved skin of the forearm. Saline and
histamine controls are injected at the same time. A result is positive for autoimmunity if the diameter of
the wheal at the serum-injected site is 1.5 mm greater than that of the bleb at the saline-injected site. The
sensitivity of this test is estimated to be 65–81% and the specificity 71–78%.[19] If a positive reaction is
observed, the result should be confirmed by in vitro testing (the gold standard), which demonstrates
histamine release from target basophils and dermal mast cells from healthy donors. [19] The ASST has also
been shown to be useful in monitoring the course of chronic urticaria, with a positive test being consistent
with an exacerbation of symptoms and a negative test with remission of symptoms.[28]
The diagnosis of chronic idiopathic urticaria is established when a patient does not have any identifiable
autoantibodies to mast cells. In these patients, the likelihood of identifying an underlying cause of the
urticaria is rare. The clinical features of autoimmune chronic urticaria are indistinguishable from those of
chronic idiopathic urticaria.
Treatment
The mainstays of managing urticaria include general measures to prevent or avoid triggers and
pharmacotherapy. Management can be stratified into first-, second-, and third-line therapies.
First-line Therapy
First-line therapy includes patient education and general non-drug measures followed by a trial of
histamine H1 receptor antihistamines if symptoms persist.[4] General measures include avoidance of
aggravating factors such as overheating, stress, and alcohol.[38] Avoidance of acetylsalicylic acid,
NSAIDs, and ACE inhibitors may also be advisable.[4,38] Cooling antipruritic lotions such as 1% or 2%
menthol in aqueous cream or calamine lotion may be helpful.[37,38] It is important to keep patients well
informed about the disease, using both verbal and written information. Specifically, patients should be
informed about the benign course of the disease, the lack of a cure, and the fact that a cause often can not
be found.[38]
Histamine H1 Receptor Antihistamines. Antihistamines are inverse agonists at H1 receptors. Stimulation
of the H1 receptor activates G-protein-coupled receptors that in turn activate inositol triphosphate and
diacylglycerol in addition to the transcription factor NF-?B, which prevents the production of many
important mediators of inflammation such as P-selectin, intercellular adhesion molecule-1, vascular cell
adhesion molecule-1, inducible nitric oxide synthase, IL-1ß, IL-6, TNFa, and GM-CSF.[64] Antihistamines
have the capacity to inhibit histamine release and prevent the actions of mast cell and basophil-derived
histamine on its target organs. H1 receptor inhibition also reduces allergen-induced eosinophil
9
accumulation. Investigators who examined the effects of two second-generation H1 receptor
antihistamines, cetirizine and levocetirizine, reported that both drugs have well documented antiinflammatory effects that include inhibition of platelet-activating factor (PAF)-dependent eosinophil
chemotaxis, PAF-dependent eosinophil adhesion to the endothelium, and transendothelial migration
through dermal endothelial cells.[65] Cetirizine has also been shown to downregulate NF-?B production.[65]
Receptor occupancy is a concept that suggests that predicting the efficacy of drugs in humans is a function
not only of the in vitro affinity of a drug to a receptor and its half-life, but also of the drug concentration at
the receptor site in vivo. For example, investigators have found that although desloratidine has a higher
affinity for H1 receptors and a longer half-life than both fexofenadine and levocetirizine, its ability to
inhibit a wheal and flare response are diminished because of decreased receptor occupancy in vivo.[66]
The efficacy of antihistamines in alleviating pruritus and decreasing the number of hives is well
established, although not all patients will respond. Of patients treated with antihistamines at tertiary care
clinics, only 40% experienced complete clearing of their symptoms.[4] In some patients, antihistamines
only reduce the severity of pruritus and decrease the number and duration of wheals.[4] However, it is
important to not assume therapeutic failure if one particular antihistamine does not resolve the urticaria;
more than one antihistamine should be tried since efficacy is patient specific. Antihistamines are most
effective if taken daily rather than on an as-needed basis.[4,38]
First-generation or classic H1 receptor antihistamines include hydroxyzine, diphenhydramine,
cyproheptadine, and chlorpheniramine (chlorphenamine). These antihistamines are rarely used as
monotherapy because of their adverse effect profile, which includes sedating and anticholinergic effects.
However, they can be valuable adjunctive therapy, especially for patients whose sleep is disturbed by
symptoms of urticaria.[4,38] Many believe that the adverse effect profile in patients with significant
urticaria is attenuated and becomes less apparent if the medication is used long term (daily for more than 1
week); however, to our knowledge, this has not been shown in any well conducted studies.
A number of second-generation H1 receptor antihistamines have been developed over the last 15 years and
are as efficacious as first-generation antihistamines. These include cetirizine, levocetirizine, loratadine,
desloratadine, fexofenadine, ebastine, and mizolastine. A major advantage of second-generation
antihistamines is their lack of significant CNS and anticholinergic adverse effects. Although
antihistamines are often prescribed at doses higher than those recommended in the package insert in an
attempt to achieve additional anti-allergenic and anti-inflammatory effects, there is no evidence to support
this practice.[67] A recent study of fexofenadine, the active metabolite of terfenadine, showed that the
recommended daily dose of 180 mg provided effective, well tolerated relief for patients with chronic
urticaria.[68] A dose-finding study by Nelson et al.[69] showed that a twice-daily 60-mg dose of
fexofenadine was only slightly less efficacious than higher doses (120 and 240 mg) in reducing pruritus
severity and number of wheals. Fexofenadine is unique amongst second-generation H1 receptor
antihistamines in that it is lipophobic and does not penetrate the blood-brain barrier; hence, it can be
prescribed at doses of up 360 mg/day without risk of sedation.[5]
Desloratadine is an active metabolite of loratadine and has more potent antihistaminic and antiinflammatory properties than loratadine.[70] Cetirizine is an active component of hydroxyzine with similar
effects but less sedation.[71] Levocetirizine is the active enantiomer of cetirizine and is more potent than
cetirizine. It has been shown to provide rapid relief of pruritus and wheals in patients with chronic
urticaria.[72] Mizolastine, which is unavailable in the US, should be used with caution in patients also
taking cytochrome P450 enzyme (CYP) inhibitors such as cimetidine, cyclosporine (ciclosporin), and
nifedipine because of concern about cardiac arrhythmias (QT prolongation).[4]
10
H2 Receptor Antagonists. Because 15% of histamine receptors in the skin are of the H2 type,[73] H2
receptor antihistamines have been shown to be a helpful addition to H1 receptor antihistamines in some
patients with chronic urticaria.[4,73,74] However, H2 receptor antagonists should not be used alone since
they have only minimal effects on pruritus. H2 receptor antagonists include cimetidine, ranitidine,
nizatidine, and famotidine.[4] Overall, data supporting the efficacy of H2 receptor antagonists are limited.
Second-line Therapy
If urticarial symptoms are not controlled by antihistamines alone, second-line therapies should be
considered, including both pharmacologic and non-pharmacologic measures. Results of phototherapy with
UV light or photochemotherapy (psoralen plus PUVA [PUVA]) have been inconclusive, although some
studies have shown increased efficacy for PUVA in managing physical urticarias but not chronic
urticaria.[75] Studies of relaxation therapies have also reported inconclusive results.[38] Several classes of
drugs may be useful in second-line therapy, including antidepressants, corticosteroids, calcium channel
antagonists, levothyroxine sodium supplements, leukotriene receptor antagonists, and a variety of other
drugs.
Antidepressants. The tricyclic antidepressant doxepin has potent H1 and H2 receptor antagonist
activity[4,37] and has been shown to be more effective and less sedating than diphenhydramine in the
treatment of chronic urticaria.[76] However, Goldsobel et al.[77] reported that sedation is a greater problem
for doxepin than for diphenhydramine or hydroxyzine and limits the usefulness of this antidepressant.
Because of its sedating properties, doxepin works best when taken at night. Furthermore, because doxepin
is metabolized by the CYP system, it should be used with caution or avoided in patients taking other drugs
metabolized by this enzyme, such as cimetidine, erythromycin, and cyclosporine. Doxepin may be
especially useful in patients with chronic urticaria and coexisting depression.[37] Although the dosage of
doxepin for the treatment of depression may vary from 25 to 150 mg/day, only 10–30 mg/day is
recommended for chronic urticaria. Mirtazapine is an antidepressant that demonstrates significant effect
on the H1 receptor and has antipruritic activity. It has been reported to be helpful in a few cases of
physical urticaria and delayed-pressure urticaria at doses of 30 mg/day.[78]
Corticosteroids. Short courses of systemic corticosteroids can be prescribed for severe urticarial
symptoms when the patient needs rapid and complete disease control. Although there is no doubt about
the efficacy of corticosteroids, long-term therapy can not be recommended because of the likelihood of
developing tolerance and numerous adverse effects such as hyperglycemia, osteoporosis, peptic ulcers,
and hypertension. If prolonged corticosteroid therapy is necessary, it is imperative to use the lowest
effective dose and incorporate corticosteroid-sparing immunosuppressive modalities.[4,37,38,74,79] Clinicians
should be aware that antihistamine dosages, particularly of first-generation antihistamines given up to four
times daily, should be maximized in an attempt to avoid corticosteroid courses.
Leukotriene Receptor Antagonists. Leukotrienes (C4, D4, E4) are potent mediators of inflammation and
have been shown to elicit wheal and flare responses both in patients with chronic urticaria and in healthy
individuals.[46] Leukotriene receptor antagonists such as montelukast, zafirlukast, and zileuton have been
shown to be superior to placebo in the treatment of patients with chronic urticaria.[80,81] Leukotriene
receptor antagonists such as montelukast may also be effective in controlling chronic urticaria in patients
who are unresponsive to antihistamines alone.[74,82,83] There is also evidence that leukotriene receptor
antagonists may prevent NSAID-induced exacerbations in patients with chronic urticaria.[84] Another
study showed that montelukast in combination with desloratadine was superior to desloratadine alone in
managing the symptoms of chronic urticaria.[85] Bagenstose et al.[86] also reported that addition of the
leukotriene receptor antagonist zafirlukast to cetirizine therapy was significantly more effective than
cetirizine alone in managing patients with chronic urticaria who were ASST positive, but not in those who
11
were ASST negative. Despite these promising results, use of leukotriene receptor antagonists in the
management of urticaria remains controversial and not all trials have shown a beneficial effect. For
example, in a recent double-blind, placebo-controlled, crossover study of 52 patients with chronic
urticaria, monotherapy with zafirlukast 20 mg twice daily did not provide any significant benefit over
placebo.[87]
Nifedipine. Nifedipine has been reported to be effective in decreasing pruritus and whealing in patients
with chronic urticaria when used alone or in combination with antihistamines.[88] Many experts, however,
have found the clinical effect of nifedipine disappointing.[38] The proposed mechanism of action is
modification of calcium influx into cutaneous mast cells. A trial of nifedipine may be a reasonable option
in patients with co-morbid hypertension, particularly if the patient is taking an ACE inhibitor or
combination therapy that includes an ACE inhibitor and an alternative antihypertensive is desired.[4,38]
Third-line Therapy
Third-line therapy for patients with urticaria who do not respond to first- and second-line treatments
typically involves the use of immunomodulatory agents, which include cyclosporine, tacrolimus,
methotrexate, cyclophosphamide, mycophenolate mofetil, and intravenous immunoglobulins (IVIG).
Patients who require third-line therapy often have the autoimmune form of chronic urticaria. Other thirdline therapies that may be beneficial include plasmapheresis, colchicine, dapsone, albuterol (salbutamol),
tranexamic acid, terbutaline, sulfasalazine, hydroxychloroquine, and warfarin.[4,16,37,38]
Immunomodulatory Agents. Several studies have shown that cyclosporine is effective in treating
patients with refractory chronic urticaria.[5,89,90] Cyclosporine 3–5 mg/kg/day appears to benefit about twothirds of patients with chronic urticaria who do not respond to antihistamines.[37] In a randomized, doubleblind trial, 8 of 19 patients with severe chronic urticaria had a positive response to cyclosporine therapy
versus none of the patients treated with placebo.[90] There was also a statistically significant decrease in
the ASST response to serum histamine-releasing activity after cyclosporine therapy. Di Gioacchino et
al.[89] reported similar results with cyclosporine in a double-blind study of 40 patients with chronic
idiopathic urticaria and a positive ASST. Greaves[5] states that >75% of patients that he treats have an
excellent response to cyclosporine with one-third remaining in remission after withdrawal, one-third
having a mild relapse, and one-third relapsing to pre-treatment levels. During treatment with cyclosporine,
H1 receptor antihistamines should be continued and blood pressure and renal function should be monitored
appropriately. Maintaining patients on long-term cyclosporine therapy should not be taken lightly because
of the numerous adverse effects of the drug (e.g. hypertension, renal toxicity) and the potential for
rebound after discontinuation.[4,37,74]
Experience with other immunomodulatory agents (tacrolimus, methotrexate, and cyclophosphamide) is
more limited.[37,74] In a recent review of the literature, Stanaland[91] reported excellent results with a 20µg/mL daily dose of tacrolimus in the treatment of patients with corticosteroid-dependent urticaria. A
recent case report described the use of intravenous cyclophosphamide to achieve complete clinical
remission in a patient with corticosteroid-dependent urticaria.[92] Methotrexate has been used successfully
in the management of two ASST-negative patients with chronic urticaria refractory to conventional
therapies.[74,93] A recent report by Shahar et al.[94] documented significant improvement in nine patients
with chronic urticaria taking mycophenolate mofetil for 12 weeks. All patients were able to stop
prednisone and no serious adverse events were noted.
IVIG appear to be effective in the management of patients with severe refractory autoimmune chronic
urticaria.[4,37,74] Although the mechanism of action involved is unclear, it has been proposed that IVIG
may contain anti-idiotypic antibodies that compete with endogenous IgG for H1 receptors and block
12
histamine release or enhance clearance of endogenous IgG.[95] Why the effect would be sustained after
initial therapy is not known. In a study by O'Donnell et al.,[96] nine of ten patients with severe autoimmune
chronic urticaria experienced clinical benefit and a reduced ASST response after 5 days of high-dose IVIG
therapy. Three patients had prolonged remissions of 3 years. Another report described complete remission
of refractory autoimmune urticaria within 48 hours after a high-dose infusion of IVIG.[95] Despite a
negative ASST at 6 months, the patient's symptoms returned 7 months after IVIG therapy. Others have not
found significant benefit.[97] Expense and potential morbidity remain concerns the use of IVIG, and
controlled studies have not yet been conducted to evaluate this therapy for urticaria.[4,37,38,74]
Plasmapheresis. Plasmapheresis has been reported to be beneficial in the management of severe chronic
autoimmune urticaria. In a case series report, plasmapheresis relieved the symptoms of six of eight
patients with severe, treatment-resistant autoimmune chronic urticaria.[98] However, this approach can not
be used long term or as monotherapy because of expense, potential morbidity, and early relapse of
urticaria. Plasmapheresis alone is insufficient to prevent re-accumulation of histamine-releasing
autoantibodies and needs to be investigated in conjunction with use of immunosuppressant
pharmacotherapy.[4,37,38,74]
Other Drugs. Dapsone[99,100] and/or colchicine[4] may be beneficial in managing urticaria when
predominantly neutrophilic infiltrates are seen histologically, but are probably most useful for urticarial
vasculitis. Limited experience suggests that sulfasalazine may be beneficial in managing both chronic
idiopathic urticaria and delayed-pressure urticaria;[4,37] however, many have not found this agent useful
and it is probably best reserved for urticarial vasculitis. Hydroxychloroquine has also shown promising
results in the treatment of chronic idiopathic urticaria; and has been associated with a good response in
hypocomplementemic urticarial vasculitis.[37,74,101] Although the ß2-adrenoceptor agonist terbutaline has
been evaluated for management of chronic urticaria, its use is generally not recommended because of
adverse effects such as tachycardia, insomnia, and jitteriness that are not well tolerated by many
patients.[79] A few studies have found that warfarin appears to have beneficial effects in some patients with
chronic urticaria;[102,103] however, other investigators were not able to replicate this finding.[104] In the
small, double-blind study conducted by Parslew et al.,[103] warfarin produced a response in some patients
with ASST-negative chronic urticaria and angioedema who were resistant to antihistamines. These results
suggest that their symptoms were not histamine dependent but more related to coagulation-dependent
mediators such as kinins.[74]
The Future
Spector and Tan[105] recently reported on three patients with chronic urticaria who responded to
omalizumab, a humanized monoclonal antibody that binds free IgE. Interestingly, not all of the patients
had elevated IgE levels prior to therapy. The investigators speculated that downregulation of IgE receptors
improved symptoms. It would be interesting to know if patients with autoimmune chronic urticaria
(patients with anti-FCeR1 antibodies) would respond similarly.
Gimenez-Arnau et al.[106] reported that treatment with a novel non-sedating H1 receptor antihistamine,
rupatadine, was associated with significant symptom improvement in 195 patients with chronic urticaria
compared with control patients. It is claimed that this antihistamine has additional anti-inflammatory
effects as a result of its anti-platelet activating factor properties and higher affinity for the H1 receptor.
Recently, H4 receptors on mast cells have been discovered. These may be more important in the
pathogenesis of itch. Knockout mice for these H4 receptors have an attenuated itch response to histamine
stimulation. Furthermore, a selective H4 receptor antihistamine, JNJ 7777120, reduced itch in mice more
effectively than H1 receptor antihistamines.[107]
13
Conclusion
Urticaria can be diagnosed on the basis of the clinical presentation without extensive laboratory
investigation and can be classified as idiopathic after allergic, infectious, physical, and drug-related causes
have been ruled out. History and physical examination are crucial while undirected laboratory
examination is typically fruitless. Although acute urticaria often has an identifiable trigger (foods, drugs,
virus), chronic urticaria frustratingly tends to remain idiopathic. About 35–40% of patients with chronic
idiopathic disease appear to have an autoimmune etiology in which setting the ASST is a somewhat
sensitive and specific test for histamine-releasing autoantibodies. These patients with autoimmune chronic
urticaria tend to follow a more aggressive course and often require more aggressive therapy. Non-sedating
H1 receptor antihistamines represent the first-line therapy for urticaria, followed by combinations of H1
receptor antihistamines with other entities such as sedating antihistamines, antidepressants, or leukotriene
receptor antagonists. For severe, recalcitrant chronic urticaria, short courses of corticosteroids can be
beneficial followed by immunosuppressant therapies for patients with debilitating disease.
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Authors and Disclosures
Tasneem Poonawalla and Brent Kelly, University of Texas Medical Branch, Galveston, Texas, USA
Disclosure: The authors have no conflicts of interest that are directly relevant to the content of this review.
Funding Information
No sources of funding were used to assist in the preparation of this review.
Am J Clin Dermatol. 2009;10(1):9-21. © 2009 Adis Data Information BV
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