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Chronic Urticaria: Practice Essentials, Background, Pathophysiology http://emedicine.medscape.

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Chronic Urticaria
Updated: May 15, 2017
Author: Marla N Diakow, MD; Chief Editor: William D James, MD more...

OVERVIEW

Practice Essentials
Urticaria is not a single disease but a reaction pattern that represents cutaneous mast cell degranulation,
with the condition being defined as chronic if lesions recur for longer than 6 weeks. Mast cell degranulation
results in extravasation of plasma into the dermis, forming characteristic hivesedematous pruritic pink
wheals of variable size and shape, with or without accompanying angioedema. In angioedema, the swelling
is deeper than wheals and may affect mucosal surfaces. Erythema is often absent in angioedema, and
typical sites of predilection include the eyelids, lips, and tongue.

In the majority of patients with chronic urticaria, no external cause or underlying disease process can be
identified. Several theories regarding the pathogenesis of chronic urticaria exist but none has been
conclusively established. It is a disease that can be frustrating to treat for both patients and caregivers, and
it can have a detrimental effect on quality of life.

Signs and symptoms

Urticarial lesions are transient in nature, with individual wheals typically lasting for less than 24 hours.
Pruritus is the most common associated symptom of chronic urticaria.

Lesions typically can be described as follows:

Primary lesions are edematous, erythematous papules or plaques with a pale center (wheal) and
surrounding erythema (flare)
Lesions may be pale to red (depending on background skin color)
Lesions can be localized or generalized
Lesions may be round, oval, annular, arcuate, serpiginous, or generalized
Lesions resolve without postinflammatory pigmentary changes or scaling

See Clinical Presentation for more detail.

Diagnosis

The diagnosis of chronic urticaria is largely clinical and based on a thorough history and physical
examination. A limited set of laboratory studies may be indicated for some patients in the diagnosis of
chronic urticaria, and these include the following:

Complete blood cell (CBC) count with differential: The eosinophil count may be elevated in patients
with parasitic infections, especially in developing countries, or in patients experiencing a drug reaction
Examination of the stool for ova and parasites: Should be considered in patients with gastrointestinal
tract symptoms, an elevated eosinophil count, or a positive travel history
Erythrocyte sedimentation rate (ESR): May be elevated in persons with urticarial vasculitis
Antinuclear antibody (ANA) titers: Indicated when urticarial vasculitis is suspected
Hepatitis B and C titers: Hepatitis B and C may be associated with cryoglobulinemia, which is
associated with some forms of cold-induced urticaria and urticarial vasculitis
Serum cryoglobulin and complement assays: Cryoglobulinemia is associated with some forms of
cold-induced urticaria

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Complement assays: C3 (associated with pulmonary involvement in a subset of patients with


urticarial vasculitis), C4 (sometimes low in hereditary angioedema), and C1-esterase inhibitor
(associated with hereditary angioedema) functional assays may be performed
Thyroid function testing and antithyroid microsomal and peroxidase antibody titers: Patients with
urticaria unresponsive to antihistamines or steroids may have elevated titers [1] ; the plasma
thyrotropin level (TSH) helps screen for thyroid dysfunction
Chronic Urticaria (CU) Index: A nonspecific measure of basophil histamine release, which, if positive,
may indicate the presence of an autoantibody to the Fc receptor of immunoglobulin E (IgE)that is,
anti-FceR. These patients are likely to have an autoimmune basis for their disease

A skin biopsy is necessary in cases of suspected urticarial vasculitis or in cases of urticaria with atypical
features on history and examination. It is also indicated for patients in whom individual urticarial lesions
persist for more than 24 hours or are associated with petechiae or purpura, as well as for patients with
systemic symptoms such as fever, arthralgia, or arthritis. A neutrophil-predominant pattern of urticaria on
biopsy may represent a subtype that does not respond well to antihistamines.

See Workup for more detail.

Management

The following medications can be used in the treatment of chronic urticaria:

Nonsedating H1 second-generation antihistamines: The mainstay of pharmacotherapy for chronic


urticaria; they decrease the intensity of hives and pruritus in patients with mild chronic urticaria
Leukotriene antagonists: Shown to be superior to placebo in the treatment of patients with chronic
urticaria but considered less effective than nonsedating antihistamines [2, 3] ; however, the 2 classes
of agents can be combined
Colchicine and dapsone: May help patients who respond poorly to antihistamine therapy or who are
known to have urticaria in which the inflammatory infiltrate is neutrophil-predominant
Systemic corticosteroids: Rarely, a short course may be prescribed for severe exacerbations of
chronic urticaria, especially when accompanied by angioedema. Long-term use for treatment of
patients with chronic urticaria should be avoided as much as possible because of the risk of adverse
effects with systemic corticosteroids
Cyclosporine and methotrexate: May benefit patients with autoimmune urticaria [4, 5]
Levothyroxine: May benefit some patients with chronic urticaria, antithyroid antibodies, or Hashimoto
thyroiditis
Omalizumab: May benefit some patients with chronic urticaria despite H 1 antihistamine treatment

See Treatment and Medication for more detail.

Background
Chronic urticaria, defined as urticaria that persists for longer than 6 weeks, is a frustrating condition for both
patients and caregivers. Urticaria is not a single disease but a reaction pattern caused by or related to
various factors, which trigger cutaneous mast cell degranulation and resulting extravasation of plasma into
the dermis.

Urticaria is characterized by hives or wheals (see images below), which are edematous pruritic papules or
plaques. The variety of potential triggers of chronic urticaria, and large number of cases without known
cause, can make the approach to diagnosis and treatment a challenge. Patients with chronic urticarial may
not improve or may depend on medication for years to relieve symptoms.

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Chronic Urticaria: Practice Essentials, Background, Pathophysiology http://emedicine.medscape.com/article/1050052-overview

Urticaria developed after bites from an imported fire ant.


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Urticaria associated with a drug reaction.


View Media Gallery

Chronic urticaria may be divided into three primary subgroups, as follows:

Physical urticaria/inducible urticaria (ie, symptomatic dermatographism, cholinergic urticaria, pressure


urticaria)
Urticaria secondary to an underlying medical condition
Chronic idiopathic urticaria/chronic spontaneous urticaria

About 20% of patients with chronic urticaria have physical urticaria, in which the appearance of lesions is
triggered by a consistent identifiable factor. Physical urticaria is reproducible with the appropriate stimuli,
and it can be identified with a thorough history, physical examination, and challenge testing. Some
examples of direct triggers include mechanical stimuli, temperature changes, sweating, stress, sun
exposure, and water contact.

When a physical etiology has been excluded, the traditional approach has been to order a panel of
laboratory tests to uncover an occult medical condition responsible for the skin findings. In many patients,
an extensive workup does not uncover an etiology. In systematic review of 6462 patients with chronic
urticaria, a causative internal medical condition was found in only 1.6% of patients [6] .Urticaria rarely is the
sole manifestation of an underlying medical problem.

The largest subset of patients with chronic urticaria encompasses patients in whom no explanation for their
urticaria is definitively established. Traditionally, these patients were said to have chronic idiopathic
urticaria; however, findings suggest that about 20-45% of such patients may have an underlying
autoimmune process driving their disease, and this specific cohort of patients is said to have chronic
autoimmune urticaria. Chronic spontaneous urticaria is a newer label used to refer to all patients with either
chronic idiopathic urticaria (55%) or chronic autoimmune urticaria (45%). [7]

An important entity in the differential diagnosis of chronic urticaria is urticarial vasculitis. A forme fruste of

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leukocytoclastic vasculitis, urticarial vasculitis may be associated with hypocomplementemia and systemic
symptoms. If urticarial lesions persist for more than 24 hours, biopsy should be performed to rule out this
entity histologically.

Pathophysiology
The mast cell is the primary agent in the pathogenesis of urticaria. Dermal mast cell stimulation results in
the release of both preformed (histamine) and newly formed (prostaglandin) mediators, as well as
cytokines (interleukin [IL]1, tumor necrosis factor- [TNF-]) from cytoplasmic granules, which cause
wheal formation, vasodilatation, and erythema. Mast cells also release chemoattractants for other cells (eg,
neutrophils) involved in wheal formation. A complex interplay of varied proinflammarory cytokines,
chemokines, and adhesion molecules that regulate vasoactivity and the dynamics of cellular infiltration
ultimately evolves to form a lymphocyte- and granulocyte-mediated hypersensitivity reaction in the skin.

This response may be augmented by complement activation and production of C5a. Unlike pulmonary
mast cells, cutaneous mast cells have C5a receptors. C5a not only brings about mast cell activation, but is
also a neutrophil and eosinophil chemoattractant, leading to accumulation of these cells in lesional skin.

Further, on a molecular level, it has been shown that there is an increased cis-to-trans urocanic acid ratio in
the epidermis of patients with chronic urticaria, which is postulated to enhance mast cell degranulation. [8]

The complex nature of the pathogenesis of urticaria beyond the release of histamine from dermal mast
cells may explain why antihistamines alone are not always effective therapy. The signals that activate mast
cells in urticaria are ill-defined and varied. A number of triggers can result in degranulation of mast cells
and initiation of the cascade that results in urticaria formation.

An autoimmune origin is one hypothesis for mast cell activation. IgE- and IgG-dependent mechanisms
include autoantibodies encompassing either IgG autoantibodies to the alpha subunit of the Fc receptor of
the IgE molecule (35-40% of patients with chronic urticaria)that is, anti-FcRor, less commonly,
anti-IgE autoantibodies (5-10% of patients with chronic urticaria), both of which can activate mast cells or
basophils to release histamine. [9] A positive functional anti-FcR test result does not indicate which
autoantibody (anti-IgE, anti-FcRI, or anti-FcRII) is present, but it does support an autoimmune basis.
Affected patients may be categorized as having autoimmune chronic urticaria.

Mast cells may also be degranulated through an IgE- and IgG-independent mechanism in chronic urticaria.
[10] NonIgE-mediated mast cell degranulators include radiocontrast media, morphine, codeine, and
vancomycin. Approximately one third of patients with chronic urticaria may develop angioedema after
administration of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs). [11]

About 85% of the histamine receptors in the skin are H1 receptors, with the remaining 15% being 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 histamine-receptor blockade has been maximized.
The combination of H2-receptor antagonists with an H1-receptor antagonist provides small additional
benefit. Doxepin blocks both receptor types and is a much more potent inhibitor of H1 receptors than
diphenhydramine or hydroxyzine.

Etiology
A number of different etiologic factors have been reported as proposed causes of chronic urticaria.

Autoimmunity is thought to be one of the most frequent causes of chronic urticaria. Various autoimmune or
endocrine diseases have been associated with urticaria, including systemic lupus erythematosus,
cryoglobulinemia, juvenile rheumatoid arthritis, and autoimmune thyroid disease (eg, Graves disease). [12,
13]

Several cross-sectional studies have investigated whether patients with chronic urticaria are more prone to
autoimmune disorders. Ryhal et al compared 25 patients with urticaria with 75 subjects being treated for
other conditions and found that antibodies to thyroid peroxidase (also known as thyroid microsomal

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antibody) and rheumatoid factor were more common in patients with chronic urticaria (P <.01 and P <.05,
respectively) compared with controls. [14] However, no difference was reported in the prevalence of other
autoantibodies, such as anti-sDNA, anti-Ro/anti-La ribonucleic acid antibodies, anti-cardiolipin, anti2-
glycoprotein 1, antimyeloperoxidase, antiproteinase 3, antismooth muscle, and antinuclear antibodies,
between the two groups. These data imply that broad nonspecific autoantibodies are not commonly found
in patients with chronic urticaria.

There is a significant association of chronic urticaria with thyroid autoimmunity, and antithyroid
autoantibodies are significantly increased in patients with chronic urticaria. The prevalence of thyroid
autoimmunity among chronic urticaria patients varies from 4.3% to 57% in the literature, and about 5-10%
of chronic urticaria patients have abnormal thyroid function. [15] In one study comparing 70 patients with
chronic urticaria with 70 healthy controls, it was found that 23-30% of patients with chronic urticaria had
either or both antithyroglobulin antibody (anti-Tg) and antimicrosomal antibody (antithyroid peroxidase
[TPO]), and as many as 5-10% had abnormal thyroid function. [15] A case control study detected similar
rates of thyroid antibodies in chronic urticaria patients, detecting anti-TG positivity in 22% and anti-TPO
positivity in 27% of chronic urticaria patients; 93% of patients had normal thyroid function. [16]

Although thyroid autoantibodies are identified more frequently in patients with chronic urticaria compared
with the general population, there is no clear evidence that management of chronic urticaria or the course
of chronic urticaria differs in this subgroup, nor is there persuasive evidence that administration of thyroid
hormone supplementation in such cases is associated with improved outcomes. Because the clinical
relevance of these autoantibodies for evaluation and treatment of patients with chronic urticaria has not
been established, routine testing for thyroid autoantibodies is not recommended. [9]

Urticaria may be caused or exacerbated by a number of drugs. Among the more common culprits are
aspirin and other NSAIDs, opioids, angiotensin-converting enzyme (ACE) inhibitors, and alcohol.

Urticaria has been reported to be associated with a number of infections; however, these associations are
not strong and may be spurious. Infectious agents reported to cause urticaria include hepatitis B and C
viruses, Streptococcus and Mycoplasma species, Helicobacter pylori, [17, 18] Mycobacterium tuberculosis,
and herpes simplex virus (HSV).

There is limited evidence that if H pylori colonization is present, eradication may result in an improvement
in chronic urticaria symptoms and thus, screening for H pylori is not recommended. [19]

The nematode Anisakis simplex is often the cause of chronic urticaria in areas where the population
frequently consumes raw or marinated fish. A report of adults seen at an allergy center in Bari, Italy, found
that 106 (50%) of 213 patients with chronic urticaria had A simplex hypersensitivity; all of the
hypersensitive patients regularly ate marinated fish. In comparison, only 16% of a control population
without chronic urticaria had sensitization to A simplex. [20] Chronic urticaria disappeared in 82 (77%) of
106 patients who gave up raw fish for 6 months; the condition cleared up in only one (2%) of 42 patients
who did not give up raw fish. Additionally, 88% who returned to eating raw fish after their condition
disappeared had a relapse of chronic urticaria, compared with 14% of those who remained on the diet. [20]

Some patients report the onset of acute urticaria associated with the consumption of certain foods, such as
shellfish, eggs, nuts, strawberries, or certain baked goods. However, food allergy is rarely the basis of
chronic urticaria.

Contactants may give rise to contact urticaria syndrome, a term referring to the onset of urticaria within
30-60 minutes of contact with an inciting agent. The lesions may be localized or generalized. Precipitating
agents include latex (especially in healthcare workers), plants, animals (eg, caterpillars, dander),
medications, and food (eg, fish, garlic, onions, tomato).

Arthropod bites or stings are the most common cause of papular urticaria. Although patients who are bitten
by mosquitoes are likely to be aware of the source of the problem, patients with scabies, bedbug bites, flea
bites, or other similar problems may not be aware. Ask patients about exposure to animals, recent moves,
hobbies, travel, or the presence of a similar skin condition in other members of the household.

Urticaria is a feature of some autoinflammatory diseases, such as Muckle-Wells syndrome (characterized

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by amyloidosis, nerve deafness, and urticaria) and Schnitzler syndrome [21] (characterized by fever, joint or
bone pain, monoclonal gammopathy, and urticaria).

Little evidence exists to support the concern that chronic urticaria may be a cutaneous sign of occult
internal malignancy. In a study of 1155 patients with chronic urticaria in Sweden, Sigurgeirsson found no
association with cancer, although acquired angioedema associated with C1 inhibitor depletion may be
associated with malignancy. [22] In a population-based cohort study in Taiwan, a slightly increased risk of
cancer, especially hematologic malignant tumor, was observed among patients with chronic urticarial. [23]
However, evidence is not sufficient to suggest any causality. Routine screening for malignancies in chronic
urticaria is not suggested; it is only warranted if patient history dictates.

In approximately 20% of cases, physical factors can be identified as a consistent cause or trigger for
chronic urticaria. The various types of physical urticaria are diagnosed by challenge testing. Several types
exist, and it is not uncommon to find that a single patient has more than one type. The following are some
of the types of physical urticaria, along with their triggers:

Dermatographism (dermographism) - Firm stroking


Delayed pressure urticaria - Pressure
Cold urticaria - Cold
Aquagenic urticaria - Water exposure
Cholinergic urticaria - Heat, exercise, or stress
Solar urticaria - Sun exposure (visible light and/or UV)
Vibratory urticaria - Vibration

Neurologic factors may play a causative role. An Italian study reported an association between chronic
urticaria and fibromyalgia, and the authors suggested that chronic urticaria may be a consequence of
fibromyalgia-neurogenic skin inflammation. [24]

Emotional and psychological factors are reported to play a role in a number of patients. Some reports cite
improvement of symptoms with hypnotism; however, the role of emotional factors remains controversial.

Hereditary angioedema is characterized by recurrent attacks of angioedema (without urticaria) involving the
skin, gastrointestinal (GI) tract, respiratory tract, and mucous membranes in a patient with a positive family
history. The disorder is autosomal dominant, and it is caused by a functional deficiency of the C1 inhibitor
protein.

Epidemiology
In the general population, the prevalence of chronic urticaria is estimated to be around 0.5-5%. Chronic
urticaria is more frequently seen in females. [9]

Patients with chronic urticaria have a strong association with HLA-DR4 and the associated allele HLA-DQ8
compared with a control population. [25]

Prognosis
The primary manifestations of urticaria are rash and pruritus. The course of the disease is unpredictable,
and it may last months to years. About 50% of patients experience remission within 1 year. [26] Only rarely
does permanent hyperpigmentation or hypopigmentation occur. The only long-term consequences of
chronic urticaria are anxiety and depression.

The prognosis in chronic urticaria depends on the comorbid disease causing the urticaria and the patients
response to therapy. Several diseases associated with chronic urticaria can be associated with significant
morbidity and mortality (eg, malignancies, systemic lupus erythematosus). Chronic urticaria can affect the
patients quality of life, owing to the associated pruritus and loss of sleep. It can lead to anxiety and
depression, with rare reports of suicide.

Clinical Presentation

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Urticaria developed after bites from an imported fire ant.


Urticaria associated with a drug reaction.

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Contributor Information and Disclosures

Author

Marla N Diakow, MD Resident Physician, Department of Dermatology, State University of New York
Downstate College of Medicine

Marla N Diakow, MD is a member of the following medical societies: Alpha Omega Alpha, American
Academy of Dermatology, American Medical Association, Women's Dermatologic Society

Disclosure: Nothing to disclose.

Coauthor(s)

Jeannette Rachel Jakus, MD, MBA Clinical Assistant Professor, Director of Clinical Research, Assistant
Program Director, Department of Dermatology, SUNY Downstate Medical Center; Dermatologist, Brody
Dermatology

Jeannette Rachel Jakus, MD, MBA is a member of the following medical societies: American Academy of
Dermatology, American Academy of Pediatrics, American Skin Association, Society for Pediatric
Dermatology, Women's Dermatologic Society

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program


Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology,

22/05/17 18.09
Chronic Urticaria: Practice Essentials, Background, Pathophysiology http://emedicine.medscape.com/article/1050052-overview

Society for Investigative Dermatology

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for:
nakedbiome<br/>Received income in an amount equal to or greater than $250 from:
elsevier;webMD<br/>editor in chief for: statpearls.

Additional Contributors

Daniel J Hogan, MD Clinical Professor of Internal Medicine (Dermatology), Nova Southeastern University
College of Osteopathic Medicine; Investigator, Hill Top Research, Florida Research Center

Daniel J Hogan, MD is a member of the following medical societies: Alpha Omega Alpha, American
Academy of Dermatology, American Contact Dermatitis Society, Canadian Dermatology Association

Disclosure: Nothing to disclose.

Acknowledgements

Warren R Heymann, MD Head, Division of Dermatology, Professor, Department of Internal Medicine,


University of Medicine and Dentistry of New Jersey-New Jersey Medical School

Warren R Heymann, MD is a member of the following medical societies: American Academy of


Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Robert A Schwartz, MD, MPH Professor and Head, Dermatology, Professor of Pathology, Pediatrics,
Medicine, and Preventive Medicine and Community Health, University of Medicine and Dentistry of New
Jersey-New Jersey Medical School

Robert A Schwartz, MD, MPH is a member of the following medical societies: Alpha Omega Alpha,
American Academy of Dermatology, American College of Physicians, and Sigma Xi

Disclosure: Nothing to disclose.

Dina D Strachan, MD Assistant Clinical Professor, Department of Dermatology, St Vincent's Medical


Center

Dina Strachan, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University
Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology,
PA

Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology,
Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association

Disclosure: Nothing to disclose.

22/05/17 18.09