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Urticaria and Angioedema


Clive EH Grattan

Anne Kobza Black


  • Hives
  • Nettle rash
  • Quincke edema (angioedema syndrome)


Key features

  • Urticaria represents transient swellings due to plasma leakage. Superficial dermal swellings are wheals and deep dermal/subcutaneous swellings are termed angioedema. Wheals are characteristically pink and pruritic, whereas angioedema is often pale and painful
  • There are several recognizable clinical patterns of urticaria and different causes. The latter include allergy, autoimmunity, drugs, dietary pseudoallergens, physical stimuli and infections. Many cases remain unexplained ('idiopathic') even after full evaluation. C1 esterase inhibitor deficiency needs to be considered as a cause of recurrent angioedema without wheals
  • Diagnosis is based mainly on the history and is supported by investigations, including blood tests, physical and dietary challenges, skin tests and skin biopsy
  • Urticaria is a common disorder that may cause considerable distress and last for years, but it can often be alleviated by appropriate management



Urticaria is a common reason for patients to present to primary care practitioners, dermatologists and allergists. It is characterized by the rapidity of its fluctuation. Individual wheals last no more than 24 hours in most patients, but the whole attack usually lasts much longer. With nearly all clinical patterns of urticaria, wheals may be accompanied by angioedema, but the occurrence of isolated angioedema (without wheals) is of special significance because some of these cases will be due to deficiency of C1 esterase inhibitor (C1 inh). The latter is a rare disorder that often runs in families and can prove fatal without treatment. Urticarial vasculitis is a systemic disease defined by damage to small blood vessels (see Chapter 26), but it may present with wheals or angioedema that without a biopsy are indistinguishable from other patterns of urticaria. Urticaria may occasionally progress to anaphylaxis, and is often a feature of that condition. Good management of urticaria depends on a thorough understanding of etiologies, triggers and aggravating factors, in addition to the most appropriate drug therapies.

Definition of Urticaria

Urticaria is often used as a descriptive term for recurrent whealing of the skin and angioedema is viewed as a separate entity, but there is logic to thinking of the two as being a continuum of clinical responses determined by the depth of swelling. Thus, urticaria may present with wheals, angioedema, or both.

Wheals are pruritic, pink or pale swellings of the superficial dermis that may have an initial flare around them ( Fig. 19.1). Lesions may be a few millimeters in diameter or as large as a hand, and numerous or single. The hallmark of wheals is that individual lesions come and go rapidly, usually within 24 hours.


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Figure 19.1 Wheals. The wheals are often pruritic, pink superficial dermal swellings that often have pale centers.


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Figure 19.2 Angioedema swellings are deeper than wheals and may affect mucosal sites. They are often pale and poorly defined.

Angioedema swellings occur deeper in the dermis and in the subcutaneous or submucosal tissue. They may also affect the mouth and, rarely, the bowel. The areas of involvement tend to be pale and painful rather than red and itchy, and last longer than wheals ( Fig. 19.2).


Urticaria has been recognized since the days of Hippocrates. The name dates back to the 18th century, when the burning and swelling of skin was likened to that caused by contact with nettles (Urtica dioica).


Estimates of the lifetime occurrence of urticaria range from less than 1% to as high as 30% in the general population, depending on the age range and method of sampling. The true figure is likely to be in the range of 1-5% 1. The prevalence of specific clinical patterns of urticaria, e.g. acute allergic or chronic idiopathic urticaria, will be lower. There is no reliable literature on racial variation, but an estimate of prevalence in China was appreciably higher than that in European studies, at 23.2% 1. Urticaria is a worldwide disease and may present at any age. The peak incidence depends on etiology. The proportion of cases due to different etiological agents is likely to relate to the frequency of environmental exposures, such as infections and allergens, in different countries, but estimates of this are not available. It is also often difficult to prove a cause and effect, and so an underlying condition may be inappropriately 'blamed' for causing urticaria. Overall, urticaria is more common in women, with a female:male ratio of approximately 2:1 for chronic urticaria, but the ratio varies with the different physical urticarias. For example, women outnumber men in dermographism and cold urticaria, but more men develop delayed pressure urticaria 2. Hereditary angioedema has an autosomal dominant inheritance pattern and occurs in approximately 1:150 000.


Basic Science

The mast cell

Distribution and diversity

The mast cell is the primary effector cell of urticaria. Mast cells are widely distributed throughout the body but vary in their phenotype and response to stimulation. This may explain why systemic features, such as those seen in anaphylaxis, do not accompany the activation of cutaneous mast cells in urticaria. The majority of mast cells in the skin and intestinal submucosa contain the neutral proteases tryptase and chymase (MC TC), whereas those in the bowel mucosa, alveolar wall and nasal mucosa contain only tryptase (MC T). Both types, however, express high-affinity IgE receptors (FcεRI) and are therefore capable of participating in IgE-dependent allergic reactions 3. There is conflicting evidence on the number of cutaneous mast cells in chronic urticaria, but there is general agreement that they may be more likely to degranulate in response to non-immunologic stimuli, such as codeine.

Degranulating stimuli

Cross-linking of two or more adjacent FcεRI on the mast cell membrane will initiate a chain of calcium- and energy-dependent steps leading to fusion of storage granules with the cell membrane and externalization of their contents. This is known as degranulation. Classic type I hypersensitivity reactions involve binding of receptor-bound specific IgE by allergen. There are several recognized immunologic degranulating stimuli that act through the IgE receptor, such as anti-IgE and anti-FcεRI antibodies. Other non-immunologic stimuli, including opiates, C5a anaphylatoxin, stem cell factor and some neuropeptides, can cause mast cell degranulation by binding specific receptors, independent of the FcεRI ( Fig. 19.3).

Proinflammatory mediators

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Figure 19.3 Mast cell degranulating stimuli.

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Figure 19.4 Medicators released by dermal mast cell degranulation. Preformed and newly synthesized proinflammatory mediators in mast cells.

Mast cell granules contain preformed mediators of inflammation, the most important of which is histamine ( Fig. 19.4). A range of cytokines has been demonstrated in human mast cells from different tissues, including tumor necrosis factor-α (TNF-α), interleukins (IL)-3, 4, 5, 6, 8 and 13, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Synthesis and secretion are upregulated following FcεRI stimulation. TNF-α is expressed constitutively in resting human cutaneous mast cells. Prostaglandins and leukotrienes are synthesized from arachidonic acid derived from cell membrane phospholipids. The most important proinflammatory eicosanoids are prostaglandin D 2 and the leukotrienes C4, D4 and E4 (slow-releasing substance of anaphylaxis). PGE 2 has inhibitory effects on mast cell degranulation and may therefore play a protective role in urticaria.

Blood vessels

Histamine and other proinflammatory mediators released on degranulation bind receptors on postcapillary venules in the skin, leading to vasodilatation and increased permeability to large plasma proteins, including albumin and immunoglobulins. Furthermore, histamine, TNF-α and IL-8 upregulate the expression of adhesion molecules on endothelial cells, thereby promoting the migration of circulating inflammatory cells from the blood into the urticarial lesion.


Humoral factors

The importance of humoral factors in the blood of urticaria patients has been increasingly recognized over the last decade. Functional IgG autoantibodies that release histamine (and other mediators) from mast cells and basophils have been detected in the serum of 30-50% of patients with chronic 'ordinary' urticaria using in vitro assays 4. The majority of these autoantibodies bind the extracellular α subunit of FcεRI. Those recognizing the α 2 domain compete with IgE for the binding site, whereas non-competitive autoantibodies directed against the terminal α 1 domain are able to bind the receptor in the presence of IgE ( Fig. 19.5). Approximately 10% of chronic urticaria sera contain functional autoantibodies directed against the Fc portion of IgE itself ( Fig. 19.3). Recent evidence indicates that binding of the autoantibodies to mast cells may initiate complement activation with the generation of C5a anaphylatoxin, which in turn facilitates or augments degranulation 5. Other mast cell activating factors may also exist in urticaria sera: a non-immunoglobulin 'mast-cell specific factor' in the cytokine molecular weight range has been described, although its identity remains unknown 6. There is currently no evidence that characterized cytokines cause mast cell degranulation in urticaria.

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Figure 19.5 Histamine-releasing autoantibodies bind the extracellular α subunit of the high-affinity IgE receptor (FcεRI). Autoantibodies directed against the terminal α 1 domain are able to bind the receptor in the presence of IgE and are therefore non-competitive, whereas those recognizing the α 2 domain compete with IgE for the binding site.

The pathogenesis of urticarial vasculitis (see Chapter 26) is thought to involve a type III hypersensitivity reaction, although the antigen has not been identified except in hepatitis B. Evidence that supports an immune complex disease includes the presence of circulating immune complexes in 30-75% of patients with urticarial vasculitis, the deposition of complement and immunoreactants in blood vessel walls, and activation of the complement cascade with generation of anaphylatoxins. In hypocomplementemic urticarial vasculitis, there is a marked and selective reduction of serum C1q 7. Autoantibodies bind to the collagen-like region of C1q, activating the complement pathway. These autoantibodies have also been described in patients with systemic lupus erythematosus (SLE).


The importance of peripheral blood leukocytes in the pathogenesis of urticaria is becoming more clear. Blood basophils in chronic 'ordinary' urticaria patients are less responsive in vitro to the immunologic stimulus anti-IgE, possibly through desensitization, and these cells are reduced in number 8. Evidence is emerging that basophils are recruited into urticarial wheals and may sustain the inflammatory response by releasing histamine and other mediators, analogous to the delayed phase of immediate hypersensitivity reactions. Eosinophil, neutrophil and lymphocyte numbers are normal in blood, but these cells are often present in biopsy specimens from spontaneous wheals. Eosinophils may contribute to the persistence of wheals by generating LTC4, D4, and E4 and releasing toxic granule proteins, including major basic protein (MBP), which can release histamine from basophils. The function of neutrophils and lymphocytes in urticaria has not been elucidated.


Substance P and other neuropeptides release histamine from mast cells in vitro and can induce a wheal and flare reaction in human skin when injected intradermally. Vasoactive intestinal polypeptide (VIP) caused a greater wheal reaction in chronic urticaria than did other skin-tested neuropeptides 9, but the relevance of this to urticaria is still uncertain.

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In Vivo Mechanisms of Urticaria

Mast cell-dependent urticaria

Potential mechanisms for mast cell-dependent urticaria are included in Table 19.1. Cross-linking of the Fab portion of specific IgE on mast cells by percutaneous or circulating allergen (type I hypersensitivity reaction; Fig 19.3) undoubtedly accounts for some cases of acute urticaria but is hardly ever the cause of chronic urticaria. Examples of this would be contact urticaria from natural rubber latex and acute urticaria from foods, including nuts, fish and fruit. However, the majority of urticaria cases do not relate closely to allergen exposure.

IgE has been implicated in the pathogenesis of dermographism, cold urticaria and solar urticaria, but the mechanism by which it renders skin mast cells more sensitive to physical stimulation is not certain 10. It is proposed that the physical stimulus in these patients induces a neoantigen that reacts with specific IgE antibody bound to mast cells. An additional mechanism such as neuropeptide release could initiate or potentiate mast cell activation. Using electron microscopy, localized platelet clumping has been demonstrated in cold urticaria, and the release of platelet mediators, including platelet-activating factor (PAF) and factor IV, could contribute to the urticaria.

Cholinergic urticaria develops in response to stimulation of cholinergic sympathetic innervation of the sweat glands. How release of acetylcholine in these patients leads to mast cell activation and histamine release is unknown. An allergy to sweat has been demonstrated by one group of investigators, but not confirmed. It has been postulated that pressure-induced wheals may be due to a late-phase reaction, but an antigen has never been identified.


Table 19-1. Etiologies and pathomechanisms of urticarial lesions.



  • Autoimmune (autoantibodies against FcεRI or IgE)
  • IgE-dependent (allergic)
  • Immune complex (vasculitic)
  • Complement- and kinin-dependent (C1 esterase inhibitor deficiency)


  • Direct mast cell-releasing agents (e.g. opiates)
  • Vasoactive stimuli (e.g. nettle stings)
  • Aspirin View drug information, other non-steroidal anti-inflammatory drugs, dietary pseudoallergens
  • Angiotensin converting enzyme inhibitors



It is often difficult to know the exact pathogenesis of individual cases of urticaria, and many cases remain idiopathic after evaluation.

The initiating event for autoimmune urticaria wheals is unknown, but may involve plasma leakage due to local factors such as heat or pressure, which allow the extravasation of autoantibodies leading to mast cell degranulation and a subsequent urticarial response. As functional autoantibodies cannot be detected in approximately 50% of chronic urticaria sera by currently available tests, other mechanisms may operate in 'non-autoantibody' urticaria which, nevertheless, has a similar clinical presentation 11. A popular hypothesis is that dietary and drug pseudoallergens may cause urticaria through the diversion of arachidonic acid metabolism from prostaglandin to leukotriene formation. How this leads to urticaria is not clear, but it is known that LTC4, D4 and E4 cause whealing on intradermal injection by a direct action on small blood vessels. There is some evidence from studies of rat peritoneal mast cells that PGD 2 and PGE 2 have inhibitory effects on immunological mast cell degranulation 12, so a reduction in their formation may facilitate the latter. Aspirin View drug informationaggravates urticaria in approximately 30% of patients with chronic disease 13, and some clinical studies of dietary pseudoallergen avoidance have given encouraging results 14. Aspirin View drug information as a cause of urticaria is much less common, and the proportion of patients with urticaria due solely to pseudoallergens is probably low. Understanding 'idiopathic' urticaria remains an important challenge. From a clinical perspective it should be regarded as a multifactorial problem, and searching for aggravating factors is just as important as looking for causes.

Mast cell-independent urticaria

There are several recognized circumstances where angioedema or wheals are due to mechanisms that do not involve mast cells. These need special consideration because their management and prognosis are different.

C1 inh deficiency is usually hereditary, but may be acquired. Hereditary angioedema (HAE) is caused by mutations in one copy of the structural gene for C1 inh, resulting in reduced levels of C1 inh (85% of cases; type 1) or C1 inh function (15% of cases; type 2) 15. Because the mutations lead to levels of 5-30% of normal (rather than the expected 50%) in patients with type 1 HAE, it is thought that there is trans inhibition of the normal allele.

The resulting deficiency allows activation of the C1 component of complement by proteolytic enzymes including plasmin and thrombin View drug information, and the generation of bradykinin by the action of kallikrein on kininogen ( Fig. 19.6). The subsequent consumption of complement leads to low levels of C4 in the serum, which is a constant and diagnostic feature between and during attacks. Acquired deficiency may result from the formation of inhibitory autoantibodies against C1 inh or persistent low-level activation of C1q by anti-idiotypic antibodies in patients with lymphoproliferative diseases, leading to consumption of C1 inh with low serum C1q as well as C4 16.

Angiotensin-converting enzyme inhibitor (ACEi)-induced urticaria is believed to result from the inhibition of endogenous kininase, although direct proof of this is lacking. It usually presents with angioedema, which is often orofacial.

Prostaglandins are involved in the pathogenesis of some patterns of non-immunologic contact urticaria (e.g. to sorbic acid), which can be suppressed by non-steroidal anti-inflammatory drugs (NSAIDs) 17.

The mediators of familial cold urticaria, familial Mediterranean fever (FMF) and Muckle-Wells syndrome have yet to be defined.


Clinical Diversity

It is important to distinguish urticaria from urticarial dermatoses such as urticarial drug eruptions and bullous pemphigoid. The wheals of urticaria are 'here today and gone tomorrow' (i.e. they last less than 24 hours), whereas urticarial dermatoses last for days or longer. Although urticarial vasculitis is usually included in classifications of urticaria because the wheals often resemble urticaria, it is actually an urticarial dermatosis. Clinically, the lesions last longer than 24 hours (as determined by circling and observing individual wheals), and histologically there is evidence of vasculitis.

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Figure 19.6 Regulatory role of C1 esterase inhibitor on the fibrinolytic, coagulation, complement and kinin systems.

Wheals may be small or large, single or multiple. In the physical urticarias the distribution pattern and morphology can be helpful in separating the different clinical types (see Physical Urticaria s). Angioedema can merge with more superficial wheals and be difficult to separate, especially around the eyelids. Angioedema can also be a feature of anaphylaxis if the throat is involved. In this sense, wheals, angioedema and anaphylaxis form parts of a clinical spectrum characterized by leakage of plasma from blood vessels with definable clinical features. In rare instances, urticaria can progress to anaphylaxis, but urticaria is often a feature of anaphylaxis.


The simplest working classification of urticaria relies on clinical characteristics rather than etiology to define groups of patients ( Table 19.2). All urticaria can be regarded as ordinary unless it has a predominantly physical trigger, evidence of vasculitis, or is caused by skin contact. Ordinary urticaria is idiopathic if no cause for it can be defined. Patients in all these groups can present with wheals, angioedema or both. Some physical urticarias and allergic contact urticaria can progress to, or present with, anaphylaxis. It is worth separating angioedema without wheals from the other patterns of urticaria because some of these cases will be due to C1 inh deficiency, ACEi or NSAID reactions, and these are managed differently from ordinary urticaria.

Acute Versus Chronic Urticaria


Table 19-2. Clinical classification of urticaria and angioedema.


  • 'Ordinary' urticaria (all urticaria not classified below)
  • Physical urticarias (see Table 19.3)
  • Urticaria l vasculitis (defined by vasculitis on skin biopsy)
  • Contact urticaria (induced by percutaneous or mucosal penetration)
  • Angioedema without wheals
  • Distinctive urticarial syndromes



All clinical patterns of urticaria can be acute, episodic or chronic.

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Figure 19.7 Causes of acute urticaria.

All urticarias are acute initially. Some will become chronic after a period of time that is usually defined as 6 weeks or more. The term 'chronic urticaria' should only be applied to continuous urticaria occurring at least twice a week off treatment. Urticaria occurring less frequently than this over a long period is better called episodic, because this presentation is perhaps more likely to have an identifiable environmental trigger. The causes of acute urticaria presenting to emergency dermatology clinics in one survey 18 are shown in Figure 19.7. Most of these cases probably fall into the ordinary category, because physical and vasculitic urticarias tend to persist beyond 6 weeks and contact urticarias would not normally present to the hospital. The high frequency of associated viral infections is notable, as is the lack of food allergy as a cause. The different clinical patterns of chronic urticaria and their causes (where known) are shown in Figure 19.8. These data reflect the experience of specialist urticaria clinics in dermatology departments and may not represent the experience of other medical practitioners, such as those in general practice, internal medicine, pediatrics, and allergy.

'Ordinary' Urticaria (Excluding Physical Urticaria and Vasculitis)

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Figure 19.8 Causes of chronic urticaria.

The condition can present at any age. Acute allergic urticaria is common in young children with atopic dermatitis, but chronic 'ordinary' urticaria peaks in the third decade. Multiple pruritic wheals of different sizes erupt anywhere on the body and then fade within 2-24 hours without bruising; angioedema lasts longer. Urticaria may occur at any time, but often appears in the evening or is present on waking. Irritation tends to be most intense at night and may disturb or prevent sleep. This, in turn, compounds the distress of the condition. Substantial impairment in quality of life measures, including self-image, sexual relationships and social interaction, has been demonstrated 19. Women may describe premenstrual exacerbations. Systemic symptoms of fatigue, lassitude, sweats and chills, indigestion or arthralgias are common with severe attacks, but the occurrence of pyrexia or arthritis should alert the clinician to another explanation, such as urticarial vasculitis or an urticarial syndrome (e.g. familial Mediterranean fever).


Chronic urticaria has been associated with autoimmune thyroid disease 20 and other autoimmune conditions, including vitiligo, insulin-dependent diabetes, rheumatoid arthritis and pernicious anemia 11. Patients with demonstrable histamine-releasing autoantibodies have a very strong association with HLA-DR4 and its associated allele HLA-DQ8 21. An association between Helicobacter pylori gastritis and chronic urticaria has been proposed but has not yet been proved by a double-blind study of eradication therapy leading to remission of urticaria. It is possible that Helicobacter infection promotes or facilitates autoantibody production by molecular mimicry 22. Parasitic infections, such as intestinal strongyloidiasis, are an uncommon cause of urticaria in developed countries but may be a significant problem where they are endemic. Acute urticaria due to gastric Anisakiasis simplex has been reported from Spain 23. Possible associations between dental infections or gastrointestinal candidiasis and chronic urticaria have not been substantiated by large epidemiologic studies. Although there have been anecdotal reports linking urticaria to malignancy, no statistically significant association was found in a large Swedish survey 24.


Schnitzler 25 in 1974 described an unusual variant of chronic urticaria comprised of recurrent non-pruritic wheals with intermittent fever, bone pain, arthralgia or arthritis, increased erythrocyte sedimentation rate (ESR) and a monoclonal IgM gammopathy. Skin biopsy specimens usually show a neutrophil-predominant dermal infiltrate, but fully developed vasculitis is uncommon. IgM may be important in wheal pathogenesis because it has been demonstrated around superficial dermal vessels in about 30% of patients, and IgM autoantibodies directed against skin have been reported 26. Some clinicians believe that these patients are best considered as having a variant of urticarial vasculitis that simply requires additional biopsies to demonstrate fully developed leukocytoclastic vasculitis.

Physical Urticarias

The physical urticarias are a distinct subgroup of the urticarias where a physical stimulus induces an urticarial reaction. They are classified according to the predominant stimulus that triggers whealing, angioedema or anaphylaxis 27 ( Table 19.3). Of all the urticarias, they may affect the quality of life most severely, particularly delayed pressure urticaria and cholinergic urticaria 28. Although most physical urticarias occur within minutes of provocation and generally resolve within 2 hours, a few physical urticarias (e.g. delayed pressure urticaria, delayed dermographism) develop after a delay of several hours and persist for 24 hours or longer.

The wheals are usually localized to the stimulated area (contact type). Sometimes a physical stimulus needs to produce a generalized body challenge, e.g. a rise or drop in core body temperature, to induce urticaria of a reflex type. Thus, generalized heating of the body can induce cholinergic urticaria, and generalized cooling, cold reflex urticaria. Here, multiple small wheals occur on widespread areas of the body. Exercise-induced anaphylaxis (EIA) and food- and exercise-induced anaphylaxis (FEIA) characteristically present with hypotension and collapse.


Table 19-3. Classification of physical urticarias by the eliciting stimulus.


Urticaria due to mechanical stimuli


  • Immediate
    • Simple
    • Symptomatic
  • Delayed

Delayed pressure urticaria

Vibratory angioedema

  • Inherited
  • Acquired

Urticaria due to temperature changes

Heat and stress

  • Cholinergic urticaria
  • Localized heat contact urticaria


  • Adrenergic urticaria


  • Cold contact urticaria
    • Primary
    • Secondary (cryoglobulins, cryofibrinogen)
  • Atypical cold urticaria

Exercise-induced urticaria

  • Exercise-induced anaphylaxis
  • Food- and exercise-induced anaphylaxis

Solar urticaria

Aquagenic urticaria


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Rare variants are not shown here for simplicity (see text).

Angioedema may be seen with all the physical urticarias except dermographism. Vibratory angioedemas manifest with subcutaneous swellings but not wheals. Also, several forms of physical urticaria can coexist in the same patient. Common combinations include dermographism and cholinergic urticaria, cold and cholinergic urticaria, delayed pressure urticaria and delayed dermographism. Delayed pressure urticaria may coexist with chronic ordinary urticaria.

Urticaria due to mechanical stimuli

Dermographism (factitious urticaria)

Immediate dermographism : This is divided into two major forms: simple and symptomatic. Simple immediate dermographism (literally 'skin writing') occurs in about 5% of normal people in response to moderate stroking of the skin and may be regarded as an exaggerated physiological response.

Symptomatic dermographism 29 is the most common of the physical urticarias ( Fig. 19.9). It manifests as linear wheals at sites of scratching and at other sites of friction, such as collars and cuffs of clothes. Whealing occurs after gentle stroking of the skin in response to a shearing force. Patients, who are most frequently young adults, often complain of pruritus before the wheals appear and may not associate them with scratching. It is worst in the evening and often occurs in bouts. The lesions usually resolve within 2 hours. Mucosal involvement does not occur, but vulval swelling with sexual intercourse has been reported.

The general course is unpredictable, but usually there is a gradual tendency towards improvement. In specialist urticaria clinics the mean duration varied from 5 to 7 years. Symptomatic dermographism very occasionally follows scabies infestation and penicillin allergy. There is no association with systemic disease, atopy, food allergy or autoimmunity.

Rarer forms of dermographism exist, including red dermographism (in response to rubbing, not stroking, the skin), localized dermographism, cholinergic dermographism, and dermographism associated with mastocytosis. The blanching response seen in patients with atopic and other forms of dermatitis, known as white dermographism, is not a form of urticaria.

Delayed dermographism: This appears at least 30 minutes after a stroking stimulus.

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Figure 19.9 Symptomatic dermographism within minutes of scratching.

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Figure 19.10 Delayed pressure urticaria on the shoulder 2 hours after carrying a heavy pipe.

Delayed pressure urticaria

Delayed pressure urticaria (DPU) is important because it can interfere severely with quality of life; it may be underdiagnosed and its treatment is difficult 30. DPU is characterized by the development of deep erythematous swellings at sites of sustained pressure to the skin, after a delay of 30 minutes to 12 hours ( Fig. 19.10). The swellings are usually pruritic, painful or both, and may persist for several days. Sites frequently involved are the waistline after wearing tight clothing, below the elastic of socks, the feet in tight shoes, the palms after manual work, the soles after walking or climbing ladders, and the genitalia after intercourse.

Systemic features such as malaise, flu-like symptoms and arthralgias may occur. If the swellings occur over joints, the resulting stiffness may be mistaken for arthritis. The prognosis is variable, but the mean duration in different series was 6-9 years. Up to 37% of patients with chronic 'ordinary' urticaria attending a hospital specialist clinic had associated DPU 31. Conversely, nearly all patients with DPU have associated chronic 'ordinary' urticaria. Because of this association and the delayed onset, patients may not be aware of any relationship to pressure unless specifically questioned.

Vibratory angioedema

This is a very rare form of urticaria where a vibratory stimulus induces localized swelling and erythema within minutes, lasting 30 minutes. Stimuli include jogging, vigorous rubbing with a towel, and the use of vibrating machinery such as lawnmowers and motorcycles. Avoidance of vibratory stimuli enables patients to live a normal life. Vibratory angioedema may be acquired or familial. The acquired form is often milder, and it may be associated with other physical urticarias such as DPU and immediate dermographism. The familial form is dominantly inherited, and intense vibratory stimuli may induce generalized erythema and headache.

Urticaria due to temperature changes

Heat and stress exposure

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Figure 19.11 Cholinergic urticaria on the trunk after exercising and sweating.

Cholinergic urticaria : This presents with multiple transient papular wheals 2-3 mm in diameter, surrounded by an obvious flare. They occur within 15 minutes of sweat-inducing stimuli, such as any form of physical exertion, hot baths, or sudden emotional stress ( Fig. 19.11). Other eliciting stimuli include moving from a cold to a hot room, drinking alcohol and eating spicy food. Although a rise in core temperature is not the only eliciting stimulus, cholinergic urticaria can conveniently be included with the physical urticarias. It occurs more frequently in young adults with an atopic tendency, and is unusual in the elderly.

After the appropriate stimulus, pruritus is followed by the development of small monomorphic wheals, distributed symmetrically. They are most prominent on the upper half of the body but can affect the lower legs and forearms and become generalized. Angioedema and systemic manifestations of faintness, headache, palpitations, abdominal pain and wheezing may occur. Reduced forced expiratory volumes without respiratory symptoms have been recorded by spirometry. In the more severely affected, it can cause severe personal and occupational disability.

Cold urticaria, dermographism or aquagenic urticaria may be associated with cholinergic urticaria. There is usually a gradual tendency towards improvement, but the condition may last for years. Rarer forms include cholinergic pruritus, cholinergic erythema (in which pruritic symmetric small erythematous macules appear to be persistent, but individual lesions actually last for up to 1 hour) and cholinergic dermographism. Severe exercise-induced cholinergic urticaria may sometimes progress to anaphylaxis.

Exercise-induced anaphylaxis (EIA) can occur without the typical wheals of cholinergic urticaria and appears to be a syndrome in its own right 32, whereas FEIA is an increasingly recognized syndrome 33. In FEIA, angioedema and/or anaphylaxis occur within minutes of exercise if it follows either prior ingestion of a specific food (e.g. wheat), or sometimes within 4 hours of a heavy meal. It may be due to priming of the mast cell by prior exposure to an allergen, or to an unknown mechanism. EIA is produced by exercise, but not by an increase in core temperature induced by other means (e.g. a hot bath) that do provoke cholinergic urticaria.

Adrenergic urticaria : This can be distinguished from cholinergic urticaria by the presence of blanched vasoconstricted skin surrounding small pink wheals induced by sudden stress. The lesions can be reproduced by intradermal injections of norepinephrine (noradrenaline). Propranolol reduces the severity, but this is also seen in cholinergic urticaria.

Localized heat contact urticaria : This is one of the rarest forms of urticaria, where within minutes of contact with heat from any source, itching and whealing occur at the precise site of contact, lasting up to 1 hour. This must be distinguished from cholinergic urticaria. Patients can present after contact with hot water (e.g. washing dishes), but also after contact with radiant heat or warm sunlight. Systemic symptoms of faintness, headache, nausea and abdominal pain have occurred. There is an even rarer delayed form.

Cold exposure

Cold urticaria represents a heterogeneous group of conditions in which whealing occurs within minutes in response to cold exposure 34.

  • Primary cold contact urticaria : The most commonly encountered form is idiopathic cold contact urticaria; it accounts for at least 95% of cases ( Fig. 19.12). Cold urticaria may follow respiratory infections, arthropod bites, and recently an association with HIV infection has been suggested. Cold urticaria may occur at any age, but it is most frequently seen in young adults. Itching, burning and whealing occur in cold-exposed areas minutes after rewarming the skin. Commonly it occurs in rainy, windy weather, and after contact with cold objects, including ice cubes. Systemic symptoms of flushing, headache, syncope and abdominal pain can develop if large areas are affected. Cold baths and swimming should usually be avoided. The mean duration was 6-9 years in one series, though primary cold contact urticaria may be more transient if it follows a viral infection.
  • Secondary cold contact urticaria : Cases due to serum abnormalities such as cryoglobulinemia or cryofibrinogenemia are extremely rare, and are then associated with other manifestations such as Raynaud's phenomenon or purpura. The wheals may last 24 hours or more. Serum cryoglobulins and cryofibrinogen should be measured, as well as serum protein electrophoresis performed. Underlying causes, such as hepatitis C or B viral infections, lymphoproliferative disease or infectious mononucleosis, should be excluded.
  • Reflex cold urticaria : In this form generalized cooling of the body induces widespread whealing. The ice cube test is negative, but placing the patient in a cold room at 4°C can reproduce lesions.
  • Familial cold urticaria : This rare condition is inherited as an autosomal dominant trait. Mutations in the same gene as Muckle-Wells syndrome on chromosome 1q44 have recently been identified 35. Burning, itching plaques that can last up to 48 hours develop as a reaction to a drop in body temperature. Fever, headache and leukocytosis may be present. It responds poorly to antihistamines and the ice cube test is frequently negative.

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Figure 19.12 Cold urticaria on an elbow after immersion in iced water for 10 minutes, followed by rewarming.

Urticaria due to other exposures

Solar urticaria

Itching and whealing occur within minutes of exposure to ultraviolet or visible wavelengths of solar radiation specific to the patient 36 (see Chapter 87). Solar radiation may penetrate light clothing. Whealing lasts for less than an hour, and headache and syncope can accompany severe reactions.

Primary solar urticaria : This is probably mediated by an immediate type I hypersensitivity reaction to a cutaneous or circulating irradiation-induced neoantigen, whereas secondary solar urticaria is seen in patients with porphyria or after tar application. It is likely that non-immunologic inflammation is induced after the absorption of radiation by the photosensitizer.

Aquagenic urticaria

In aquagenic urticaria, contact with water of any temperature induces an urticarial eruption resembling a sparse form of cholinergic urticaria. Lesions occur most frequently on the upper part of the body and last for less than an hour. Other physical urticarias must be excluded and the condition must be differentiated from aquagenic pruritus (see Chapter 7).

Urticaria l Vasculitis

Urticaria l vasculitis is a clinicopathological entity in which cutaneous lesions resemble urticaria clinically (but last longer than 24 hours) and histologically show evidence of vasculitis (venulitis; see Chapter 26) 37. The histological diagnosis is dependent on examination of a representative lesion, preferably of less than 12 hours' duration (see Pathology). The incidence varies from between 2 and 20% of chronic urticaria, depending on the criteria for histologic evidence of vessel damage. A realistic figure appears to be 5-10%. Urticarial vasculitis is more common in middle-aged women, though, unusually, it can occur in children.

Although in practice it is difficult to differentiate the wheals of urticarial vasculitis from those of 'ordinary' urticaria, the former tend to be more persistent (lasting more than 24 hours) and may burn and be painful as well as pruritic. They often occur at pressure points and may resemble delayed pressure urticaria ( Fig. 19.13). Lesions resolve with residual purpura in a minority of patients. Rarer dermatological manifestations include livedo reticularis and erythema multiforme-like lesions. Angioedema occurs in up to 40% of patients, as in chronic 'ordinary' urticaria.

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Figure 19.13 Lesions of urticarial vasculitis that look like ordinary urticaria but which last longer and may bruise.

The most common extracutaneous manifestation is arthralgias (affecting 50% of patients), but they are usually transient and migratory. Frank arthritis is rare. However, there is a greater incidence of systemic manifestations in hypocomplementemic patients. Gastrointestinal involvement (seen in approximately 20%) manifests as abdominal pain, nausea, vomiting and diarrhea. A similar percentage develops pulmonary obstructive disease, particularly in smokers. This may not occur until late in the disease, but can be the most life-threatening complication. Renal disease presenting as proteinuria or hematuria occurs in 5-10% of patients, but in the absence of associated connective tissue disease progression to severe renal disease is unlikely. Rarer manifestations include Raynaud's phenomenon, splenomegaly, lymphadenopathy, conjunctivitis, episcleritis, uveitis, pseudotumor cerebri, and muscle and pericardial involvement.

The course is unpredictable but, overall, the disease has a relatively benign course lasting an average of 3 years, though it can persist for many years. Patients with hypocomplementemia tend to have more frequent and severe systemic involvement and the course is less favorable.


In the great majority of patients the etiology is idiopathic. A small minority is associated with systemic lupus erythematosus (SLE), Sjögren's syndrome, serum sickness, and infections including hepatitis B and C, Lyme disease and infectious mononucleosis. Rarely it may be linked with a drug (e.g. cimetidine, diltiazem), hypergammaglobulinemia, hematologic disorders, or solar and cold urticaria.


A few patients with Schnitzler's syndrome do show a small vessel venulitis on histologic examination. A variant of urticarial vasculitis with prominent cutaneous hemorrhage has been described in very young children, known as acute hemorrhagic edema of childhood (see Chapter 26).

Contact Urticaria

Contact urticaria is usually defined by the development of urticaria at the site(s) of contact with skin or mucosa, but contact erythema and even burning and stinging without erythema are sometimes embraced in the definition 17. Percutaneous or mucosal penetration of the urticant may have distant effects, including acute urticaria or even anaphylaxis. Contact urticaria is probably very common but does not often present to hospital or tertiary care clinics because the diagnosis is usually self-evident.

Immunologic and non-immunologic types are recognized depending on whether the contact urticaria is due to allergen interaction with specific IgE or is IgE independent. In this sense, contact urticaria is either allergic or non-allergic. Allergic contact urticaria can be seen in children with atopic dermatitis who are sensitized to environmental allergens, such as grass, animals and foods, or glove-wearers who are allergic to latex ( Fig. 19.14). In those individuals repeatedly exposed to latex via mucosal surfaces (e.g. urinary catheterization in spina bifida patients), allergic contact urticaria can be complicated by anaphylaxis. Non-immunologic (non-allergic) contact urticaria is due to direct effects of urticants on blood vessels, such as sorbic acid and benzoic acid in eye solutions and foods, cinnamic aldehyde in cosmetics, or histamine, acetylcholine and serotonin in nettle stings ( Fig. 19.15). It may also result from chemicals, known as histamine liberators, that degranulate mast cells, e.g. dimethylsulfoxide and cobalt chloride.

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Figure 19.14 Allergic contact urticaria (arrows) to latex from a rubber glove.

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Figure 19.15 Non-immunological contact urticaria from a nettle sting.

The time course, duration and response to mediator antagonists will depend on which mediators are involved in its pathogenesis. Contact urticaria due to mast cell degranulation or nettle stings appears within minutes, is partially inhibited by antihistamines and usually fades within 2 hours, whereas non-immunologic contact urticaria may take 45 minutes to appear and is inhibited by non-steroidal anti-inflammatory drugs (NSAIDs).


The only entity associated with allergic contact urticaria is atopic disease in which the development of specific IgE to naturally occurring allergens is a constant feature.


The oral allergy syndrome presents with itching and mild swelling of the mouth, tongue and soft palate within minutes of eating fresh fruits such as apples, pears, peaches and cherries, but not cooked fruits. It usually occurs in hayfever sufferers and is probably a cross-reaction between birch pollen and fruit proteins 38. Angioedema and anaphylaxis are fortunately very rare with this form of allergic contact urticaria.

Angioedema Without Wheals

Recurrent angioedema without wheals is in many instances idiopathic, but it is always important to exclude a drug reaction and to consider the possibility of C1 inh deficiency.

Drug reactions

A number of drugs can cause angioedema without wheals. The most common are NSAIDs 39 and angiotensin-converting enzyme inhibitors (ACEis) 40. Aspirin View drug information intolerance may present with angioedema alone, or with urticaria or anaphylaxis. Cross-reactions with other NSAIDs can occur. A link with ACEi therapy may be overlooked because initial reactions can appear over a year after starting the medication. For practical purposes, ACEis should be discontinued in favor of other antihypertensive medications if angioedema without wheals or urticaria occurs; ACEis are contraindicated in patients with C1 inh deficiency.

C1 esterase inhibitor deficiency

The likelihood of C1 inh deficiency as a cause of recurrent angioedema is increased if there is a family history or previous laryngeal edema or colicky abdominal pain sometimes presenting as a surgical emergency. Trauma (emotional or physical) can trigger attacks. The usual duration is 48-72 hours and episodes are often followed by a refractory periods. Some families with hereditary angioedema describe a transient erythematous prodromal rash, but urticarial whealing does not occur and so a history of recurrent wheals effectively excludes the disorder.


Acquired C1 inh deficiency has been associated with SLE, paraproteinemia and lymphoproliferative disease.


A syndrome of episodic angioedema with hypereosinophilia, weight gain and fever has been described. The cause is uncertain, but increased serum levels of IL-5 have been found 41.

Distinctive Urticarial Syndromes

Muckle-Wells syndrome

This rare autosomal dominant condition is characterized by recurrent urticaria from birth, with chills, fever and malaise. Progressive sensorineural deafness develops, as does amyloidosis in about one-third of patients, including kidney involvement. Elevated serum IL-6 levels have been reported. Mutations in the same gene as familial cold urticaria occur.

Familial Mediterranean fever

Inheritance is autosomal recessive, with a predilection for Sephardic Jews, Armenians and Arabs. It has some clinical similarity to Muckle-Wells syndrome in that erythematous and urticarial skin lesions are associated with fever and amyloidosis. Patients may present with peritonitis, pleurisy or synovitis.

Systemic capillary leak syndrome

Also known as Clarkson syndrome, this rare acquired disorder is characterized by episodic massive plasma exudation from blood vessels, leading to potentially life-threatening hypotension, analogous to anaphylaxis. Angioedema may be a feature. It is associated with an IgG paraproteinemia. Medications, in particular IL-2, can also produce a systemic capillary leak syndrome.


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Figure 19.16 Histology of a spontaneous wheal showing dermal edema, a dilated vessel, and a mild perivascular infiltrate of lymphocytes, neutrophils and eosinophils.

The histopathology of urticaria is classified as a dermal hypersensitivity reaction and is characterized by a perivascular infiltrate of lymphocytes and eosinophils ( Fig. 19.16), with extension of eosinophils into the dermis, arrayed between collagen bundles. The density of inflammatory cells is usually scant. The identification of dermal edema is highly subjective. A predominantly neutrophilic pattern has been described in a minority of patients, but this does not appear to carry any diagnostic significance 42. Previous reviews of biopsy specimens from large series of patients with urticaria have emphasized a spectrum of changes, ranging from mild lymphocytic infiltrates to fully developed leukocytoclastic vasculitis 43. Features of the latter include endothelial cell swelling, a perivenular cellular infiltrate rich in neutrophils, extravasation of red cells, leukocytoclasis, and fibrinoid deposits in and around blood vessels. The last two criteria are the most important, as they demonstrate blood vessel damage. A predominantly lymphohistiocytic infiltrate is unusual. Direct immunofluorescence of the wheal frequently shows deposition of immunoglobulins and complement C3 within blood vessels, which is a non-specific finding.


The differential diagnosis includes all dermatologic conditions with an urticarial component, including cutaneous mastocytosis ( urticaria pigmentosa), urticarial vasculitis, insect bite reactions (papular urticaria), acute febrile neutrophilic dermatosis (Sweet's syndrome), pre-bullous pemphigoid (i.e. urticarial bullous pemphigoid), acute facial contact dermatitis and urticarial drug reactions (e.g. antibiotics). In all these conditions the urticarial component is part of a more prolonged inflammatory process (or mast cell proliferation in the case of mastocytosis) than true urticaria and should be readily distinguishable by the prolonged duration of individual lesions.


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Figure 19.17 Approach to the diagnosis of chronic urticaria.

A comprehensive history is essential in every patient with urticaria. It should cover the duration of disease, frequency of attacks, duration of individual lesions, associated illness, previous treatment, known adverse reactions, past and family history, occupation and leisure activities, and an assessment of the impact of the disease on the patient's quality of life. The use of a detailed questionnaire in conjunction with a complete blood count and ESR was found to be almost as good as a complete diagnostic evaluation 44. A full examination looking for the morphology and duration (by circling individual lesions) of wheals, bruising, livedo reticularis and signs of systemic disease should always be undertaken, but is often normal. The patient's own photographs can often be useful because it is common for urticaria to have cleared by the time of consultation. Investigation should be targeted at specific features identified in the clinical assessment, as outlined below, and may include blood tests, skin biopsy (obtained in all patients with lesions lasting more than 24 hours), challenges for physical urticarias, food additives and drugs, and, infrequently, skin tests for allergy and the measurement of histamine-releasing autoantibodies. Most cases of antihistamine-responsive urticaria do not need investigation. A diagnostic algorithm is given in Figure 19.17.

Acute urticaria

IgE-mediated reactions to environmental allergens as a cause of acute urticaria and contact urticaria can be confirmed by skin prick testing and radioallergosorbent tests (RAST) of blood. Results of both have to be interpreted in the clinical context.

Chronic 'ordinary' urticaria

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Figure 19.18 A pink wheal response is present at the site of an intradermal injection of autologous serum, but not at that of a normal saline control. Spontaneous wheals are also present at the venipuncture site and away from the skin tests.

No investigations are required for the majority of patients with mild disease that responds to antihistamines. A useful screening profile for non-responders with more severe disease could include a complete blood count and white cell differential (for instance to detect the eosinophilia of intestinal parasitosis) and ESR (usually normal in chronic urticaria, but may be raised in urticarial vasculitis). Thyroid autoantibodies should be considered and thyroid function tests performed if indicated clinically. A history and physical examination can be performed by a primary care physician, and evidence of Helicobacter infection can be sought in patients with dyspeptic symptoms. There is currently no routine laboratory test for histamine-releasing autoantibodies. However, in centers with experience in the procedure, a reasonably sensitive and specific screening test 45 for basophil histamine release is the response to an intradermal injection of autologous serum: the test is positive when there is a pink wheal that is at least 1.5 mm greater in diameter than that caused by an adjacent saline control injection ( Fig. 19.18).

Physical urticarias

International standards for the diagnosis of physical urticarias and definitions of challenge testing have been proposed 31. Dermographism can be tested for easily by stroking the skin of the back lightly with the rounded edge of a wooden spatula. A calibrated instrument called a dermographometer, which is a spring-loaded stylus the pressure of which can be adjusted to a predetermined setting, can quantify the sensitivity of the skin. Delayed pressure urticaria is confirmed if application of a standardized weight to a defined area of skin for a specified time results in a palpable wheal at 2-8 hours (usually at 6 hours). Provocation tests for cholinergic urticaria include exercise to the point of sweating in an overheated environment, or partial immersion in a hot bath at 42°C for 10 minutes. The latter test excludes exercise-induced anaphylaxis. Cold contact urticaria is confirmed by the development of whealing at the site of application of an ice cube in a plastic bag.

Phototesting confirms the diagnosis of solar urticaria, with the development of wheals within minutes of exposure to natural or artificial radiation. The action spectra of the inducing wavelengths can be determined by narrowband monochromators (see Chapter 87). The diagnosis of aquagenic urticaria is made by inducing wheals after a bath or shower at body temperature, or under wet gauze applied at body temperature for 20 minutes. Localized heat urticaria is confirmed by applying a heated cylinder (temperature varies between 43 and 56°C) to the skin for 5 minutes.

Urticaria l vasculitis

Lesional skin biopsy is essential and should be undertaken for the circled lesions that last more than 24 hours to confirm the presence or absence of leukocytoclastic vasculitis histologically (endothelial cell damage, leukocytoclasia and fibrin deposition are cardinal features). Patients with urticarial vasculitis need a full vasculitis screen, including serum complement assays and the exclusion of systemic lupus erythematosus (SLE). Evaluation of systemic involvement includes a complete blood count, ESR, urinalysis, tests for renal and liver function, serum complement levels C3, C4 and CH50 (and, if C4 is low, C1q), pulmonary function tests, and chest X-ray if appropriate. Investigations for possible associated diseases include serum antibodies for SLE, serum immunoglobulins and electrophoresis, cryoglobulins, hepatitis B and C viral serologies, and Borrelia antibody tests. The more common abnormalities in the largest series to date of 132 patients was an elevated ESR (28%), hypocomplementemia (18%; usually of C3 and C4), and a positive antinuclear antibody (ANA) of low titer (35%) or >1:160 titer (11%). Although hematuria was found in 29%, after excluding urinary infections, renal disease was present in only 5.5% 46.

Angioedema without wheals

Testing for low serum C4 is a very sensitive but non-specific screening test for hereditary and acquired C1 inh deficiency. Measurement of the amount of C1 inh by immunochemical assay for type I deficiency and C1 inh function to detect type 2 deficiency should be requested if indicated by the history and supported by a low serum C4 level. C1q will also be reduced in acquired C1 inh deficiency.


Patients should be given advice and information on common precipitants, treatments and prognosis. Antipruritic lotions and the avoidance of aggravating factors, including NSAIDs, may be sufficient for some, but many will need additional interventions, including systemic medications. These can stratified into first-, second- and third-line therapies ( Fig. 19.19). The management of urticarial vasculitis and C1 inh deficiency is considered separately because their pathogenesis and response to treatment are different. Patients must understand that although systemic corticosteroids may be the only treatment that completely eliminates their lesions, long-term use is unacceptable and combinations of other therapies can control symptoms and significantly improve quality of life.

Ordinary and Physical Urticarias

First-line therapies

Antihistamines are the mainstay of management for most cases of urticaria, although not all patients will respond and only about 40% of those attending tertiary care clinics will clear or almost clear on treatment. Antihistamines may reduce pruritus, flatten wheals, shorten wheal duration and reduce wheal numbers even though they may not clear urticaria completely. It is worth discussing the relative benefit with patients who feel that 'they haven't worked'.

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Figure 19.19 Management of ordinary and physical chronic urticaria.

Antihistamines should be taken on a daily basis, the frequency depending on their half-life. In other words, they should not be taken only when the patient is symptomatic. As a general rule, antihistamines are safe and have few significant adverse effects 47. They can be grouped into first-generation (classic) antihistamines, second-generation (non- or minimally sedating) antihistamines, third-generation derivatives, and the H 2 antagonists ( Table 19.4). Some controversy remains as to whether the term 'third-generation' is justified. Combining drugs from the different groups can lead to better control of urticaria symptoms.

Classic antihistamines


Table 19-4. Antihistamines for chronic urticaria.




Daily adult dose*

Classic (sedating)

Chlorpheniramine (1)

4 mg three times daily (up to 12 mg at night)

Hydroxyzine View drug information (1)

10-25 mg three times daily (up to 75 mg at night)

Diphenhydramine (2)

10-25 mg at night


Acrivastine (1)

8 mg three times daily

Cetirizine (1)

10 mg once daily

Loratadine View drug information (1)

10 mg once daily

Mizolastine (1)

10 mg once daily


Desloratadine (1)

5 mg once daily

Fexofenadine (1)

180 mg once daily

H 2 antagonists

Cimetidine (1)

400 mg twice daily

Ranitidine (2)

150 mg twice daily




* Current prescribing manuals should be consulted for details on doses in children.
A short-acting classic antihistamine may be added at night to a daily second- or third-generation antihistamine, with or without the addition of an H 2 antagonist for maximal antihistamine blockade.
( ) = evidence category: 1, double-blind study; 2, clinical trial.

Classic antihistamines are not often used as monotherapy nowadays because sedation and the anticholinergic side effects are often dose limiting. However, in combination with a daytime non-sedating antihistamine they can be valuable at night if sleep is disturbed by urticaria. Short-acting sedating antihistamines, such as chlorpheniramine and hydroxyzine View drug information, are usually preferable to longer-acting drugs, such as diphenhydramine, which may interfere with skilled tasks the following day (e.g. operating machinery and driving). Short-acting classic antihistamines still have a place in the primary management of urticaria in children between 1 and 6 years of age, and during pregnancy. Chlorpheniramine is often chosen for pregnant women when antihistamines are essential because it has a long safety record; however, it is not licensed for this indication and should be avoided in the first trimester if possible.

Second-generation antihistamines

Second-generation antihistamines are usually well tolerated and simple to take, the majority of patients requiring only once-daily oral dosing ( Table 19.4). For chronic urticaria there is probably little to choose between the second-generation antihistamines when taken at the licensed dose. It has become common practice to increase the daily dose of loratadine View drug information and cetirizine to 20 or 30 mg for difficult urticaria on the grounds that their additional anti-allergic and anti-inflammatory properties may be clinically beneficial at these higher doses. Controlled evidence for this is lacking, however. Acrivastine is a short-acting non-sedating antihistamine that is taken every 8 hours but is only available in the US as a combination product with pseudoephedrine for seasonal allergic rhinitis. Mizolastine is currently not available in the US.

Clinically important drug interactions are infrequent, but co-administration of mizolastine with systemic erythromycin View drug information and ketoconazole View drug information is contraindicated because of concern about possible cardiac arrhythmias (as with terfenadine and astemizole before it). Caution is also recommended with regard to other hepatic cytochrome P450 3A4 inhibitors or substrates (see Chapter 132), including cimetidine, cyclosporine View drug information and nifedipine View drug information, all of which may be used for urticaria in special circumstances.

Third-generation antihistamines

Fexofenadine is the first of the third-generation antihistamines and is licensed for urticaria at 180 mg daily. It is the active metabolite of terfenadine. It does not appear to have the potential for ventricular arrhythmias of its parent drug at licensed doses, but it is prudent not to exceed them until more is known about the effects of increased drug concentrations in large populations. Desloratadine View drug information, an active metabolite of loratadine View drug information, with more potent antihistaminic and anti-inflammatory properties than its parent, has recently become commercially available. It is taken at a smaller daily dose (5 mg) for chronic urticaria, but it is not yet clear whether it offers a clinical advantage.

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Addition of H 2 antagonists to conventional H 1 antihistamines

The addition of H 2 antagonists to conventional H 1 antihistamines may be helpful in some patients with chronic urticaria. However, H 2 antagonists have no effect on histamine-induced pruritus and should not be used on their own. Cimetidine has the slight disadvantage of potential interactions with drugs that share oxidative hepatic metabolism, including warfarin, mizolastine, diazepam View drug information and propanolol. In men, gynecomastia and azoospermia may occur but are reversible upon discontinuation. Ranitidine is also effective and is preferable to cimetidine because it does not interfere with hepatic metabolism and does not bind androgen receptors. Nizatidine View drug information and famotidine View drug information have similar properties to ranitidine, but have not been evaluated in clinical trials for chronic urticaria and cannot be specifically recommended. Feedback inhibition of mast cells is dependent on H 2 receptors on mast cells, therefore H 2 antihistamines should not be used as monotherapy.

Second-line therapies

There are many possible second-line drugs to consider when urticaria does not respond well to antihistamines, but high-quality evidence-based trials to support their use are hard to find. Non-drug interventions involving diet and phototherapy can also be considered. The choice of second-line drugs should be guided by specific indications, summarized in Table 19.5. Here the management of urticaria can be influenced considerably by a full clinical assessment and the experience of the clinician. It is unusual for children to need second-line therapies, except the occasional use of prednisone View drug information for very severe acute exacerbations of chronic urticaria. Second-line drugs should be used with considerable care in pregnancy, and only after the risks have been carefully considered against the likely benefits.

Drug therapies

Doxepin is a tricyclic antidepressant with very potent antihistaminic properties. Although it has significant sedative properties and is preferably administered at bedtime, doxepin is a common component of combination therapy regimens, especially in patients with chronic ordinary urticaria.

Prednisone View drug information or prednisolone View drug information is effective for nearly all presentations of chronic urticaria but often needs to be used at high doses (30-40 mg daily) to achieve good initial control of severe disease. It should be considered mainly for the short-term management of 'crisis' urticaria and serious angioedema of the throat when, often, a single dose or several daily doses will be sufficient to re-establish control with regular full-dose antihistamines. Regular treatment with oral corticosteroids should be avoided because of the prolonged duration of chronic idiopathic urticaria and because of their predictable side effects (hypertension, weight gain, glucose View drug information intolerance, osteoporosis). Some authorities advise alternate-day dosing to minimize the adrenal suppression than can occur with long-term administration.

Epinephrine View drug information (adrenaline) is not often required in chronic ordinary urticaria where angioedema of the throat is rarely severe enough to be life threatening, but it can be reassuring for patients to carry an epinephrine View drug information pen for self-administration if they are prone to bad attacks. Epinephrine View drug information is the treatment of choice for anaphylaxis, whether it is due to an allergy, pseudoallergy or physical urticaria. Directing epinephrine View drug information mist from an aerosol inhaler on to mucosal angioedema may be helpful for minor episodes, but it is usually better to administer treatment intramuscularly or subcutaneously if any is required. Side effects of epinephrine View drug information include tachycardia, anxiety and headache. It should be used with caution in patients with hypertension, ischemic heart disease, cerebrovascular disease and diabetes mellitus. Co-administration of tricyclic antidepressants (including doxepin) and β-blockers should be avoided.

Nifedipine View drug information has been shown in several blinded studies to be helpful for chronic urticaria, either alone or in combination with antihistamines, although it tends to be disappointing. It is nevertheless worth trying for patients with urticaria and hypertension, and may serve as a single therapy for both conditions. Modified-release versions are now available for the long-term management of hypertension. Side effects include headache, flushing, postural hypotension and gravitational edema. Other calcium antagonists have not been carefully studied for urticaria and are probably best avoided.

Thyroxine supplementation has been reported to suppress chronic idiopathic urticaria in biochemically euthyroid patients with antithyroid autoantibodies. Although there may be occasional successes from this approach the results are inconsistent. There is a slight anxiety that osteoporosis might be promoted in biochemically euthyroid postmenopausal patients on long-term treatment.


Table 19-5. Some second-line medications for chronic or physical urticaria.


Generic name

Drug class



Special indication/associated diseases

Doxepin (1)

Tricyclic antidepressant


10-75 mg qhs


Prednisone View drug information (2)



0.5 mg/kg qd

Severe exacerbations (days only)

Epinephrine View drug information (2)


SC, IM (self-administered)

300-500 μg

Angioedema of throat or anaphylaxis

Nifedipine View drug information (1)

Calcium antagonist


10-40 mg modified-release qd


Thyroxine (2)

Thyroid hormone


50-150 μg qd

Autoimmune thyroid disease

Montelukast (1)

Leukotriene receptor antagonist


10 mg qd

?Aspirin-sensitive urticaria or pressure-induced urticaria

Colchicine View drug information (3)

Neutrophil inhibitor


0.6-1.8 mg qd

Neutrophilic infiltrates in lesional biopsy specimens

Sulfasalazine View drug information (3)



2-4 g qd

Associated delayed pressure urticaria


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Current prescribing manuals should be consulted for details on dose, drug interactions and contraindications for individual patients. The stated doses represent guidelines only. ( ) = evidence category: 1, double-blind study; 2, clinical trial; 3, anecdotal case reports.

Montelukast may be beneficial for aspirin-sensitive chronic urticaria in view of the likely involvement of leukotrienes in its pathogenesis, and a recent study supports this 48. Zafirlukast has also been used. There have been anecdotal reports of responses in refractory chronic urticaria associated with delayed pressure urticaria, but clinical experience to date has been less encouraging. Side effects are uncommon, but urticaria, angioedema and anaphylaxis have been reported when it has been given for other indications.

Colchicine View drug information may be beneficial for chronic urticaria when predominantly neutrophilic infiltrates are seen histologically ('neutrophilic urticaria') and is also used for urticarial vasculitis. Side effects include nausea, vomiting and abdominal pain. Peripheral neuritis, myopathy, alopecia and blood disorders have been reported rarely with prolonged treatment.

Sulfasalazine View drug information can be helpful for chronic urticaria where delayed pressure urticaria (DPU) symptoms predominate, provided it is tolerated. These patients often require systemic corticosteroids otherwise. The drug should be avoided in patients with aspirin View drug information sensitivity and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Complete blood count and hepatic enzymes must be monitored monthly for the first 3 months, and then regularly during therapy. Stevens-Johnson syndrome, nephrotic syndrome and oligospermia have been reported.

Non-steroidal anti-inflammatory drugs have been used to treat DPU, with conflicting results, but may exacerbate ordinary chronic idiopathic urticaria.

Anabolic steroids , such as danazol View drug information, may be useful for severe cholinergic urticaria, but virilizing side effects and long-term concern regarding liver toxicity are disadvantages.

Miscellaneous Other drug therapies described for chronic urticaria include tranexamic acid View drug information, terbutaline and warfarin, but convincing evidence for their use is lacking and there are no specific situations where they appear to be better than other treatments.

Non-drug therapies

Exclusion of food additives and natural salicylates from the diet has been advocated in a number of reports. The high success rates in some series may have been due in part to the natural history of remission in chronic urticaria, as less than 20% of patients responding to low-pseudoallergen diets flare after double-blind placebo-controlled challenge with individual additives 14. Diets nevertheless remain popular with chronic urticaria patients and are always worth considering when antihistamines have failed and second-line drugs are inappropriate. There is general agreement that food allergy as a cause of chronic urticaria is exceptional, and that investigation for relevant immediate hypersensitivity reactions should not be undertaken without a strong lead from the history.

Induction of tolerance by repeated frequent graduated exposures to the precipitating physical factor can be helpful for cold urticaria, solar urticaria and localized heat contact urticaria. The schedule is time consuming, not all patients can be rendered tolerant, and repeated daily exposures are necessary to maintain tolerance.

Phototherapy with ultraviolet light or photochemotherapy (PUVA) has been used for chronic urticaria but the reported results have been inconclusive. A recent retrospective survey suggested that narrowband ultraviolet B phototherapy might be effective. PUVA may be helpful for the pruritus of highly symptomatic dermographism, although whealing is not usually improved.

Third-line therapies

The recognition that some patients with severe urticaria unresponsive to antihistamines have an autoimmune etiology has opened up the option of immunotherapy for selected cases of chronic autoimmune urticaria. Cyclosporine View drug information and plasmapheresis have been used successfully in some of the most severely affected patients with solar urticaria.

Plasmapheresis was successful in some patients with chronic autoimmune urticaria in a small open study, but it is not recommended as monotherapy because of its expense, its potential morbidity, and the early relapse of the urticaria 49.

Intravenous immunoglobulin infusions (total 2 g/kg in total over 5 days) were beneficial to the majority of chronic autoimmune urticaria patients in another small open study, with remissions in some lasting at least 3 years 50. Expense and potential morbidity remain a concern for this approach, which has not been subject to controlled studies.

Cyclosporine View drug information at 3-5 mg/kg/day appears to clear or substantially benefit approximately two-thirds of patients with chronic autoimmune urticaria refractory to antihistamines. This benefit has now been confirmed in a double-blind study of cyclosporine View drug information at 4 mg/kg/day for 4-8 weeks; there were no serious adverse effects (e.g. renal impairment) 51. However, only 25% of responders remained clear or almost clear 4-5 months after discontinuing therapy, and symptomatic side effects (e.g. gastrointestinal) were common. In addition, the risk of maintaining the 'impossible to wean' patient on long-term cyclosporine View drug information is potentially considerable, as is the risk of rebound after discontinuation. Optimal treatment protocols have still to be confirmed.

Urticaria l Vasculitis

There are no randomized trials of treatment modalities for urticarial vasculitis and no universally effective therapy. The variation in individual responses possibly reflects the spectrum of disease. Antihistamines are usually insufficient except in the mildest cases. They can be continued in addition to other treatments, as patients frequently suffer pruritus. Non-steroidal anti-inflammatory drugs lead to improvement in approximately 50% of patients. There are isolated reports that colchicine, dapsone and antimalarials may benefit some patients, but the response is unpredictable. Pentoxifylline, reported to be effective in combination with dapsone, has been disappointing. Most patients benefit from systemic corticosteroids, which may be the only treatment effective in hypocomplementemic urticarial vasculitis. Systemic corticosteroids may be combined successfully with immunosuppressants such as azathioprine, cyclophosphamide and mycophenolate mofetil; methotrexate can be used on its own. Plasmapheresis has temporarily improved some patients.

C1 Esterase Inhibitor Deficiency

The treatment of C1 inh deficiency differs from that of other types of angioedema. C1 inh concentrate or fresh frozen plasma should be given in an emergency, as it may prove to be life saving. Antihistamines, corticosteroids and epinephrine View drug information are said not to be adequate in patients with C1 inh deficiency. C1 inh concentrate may also be given as prophylaxis before surgery, especially when intubation or tooth extraction is necessary. Tranexamic acid View drug information given for 3-4 days before procedures, or an increase in established maintenance doses of tranexamic acid View drug information or anabolic steroids, can be effective prophylaxis for minor surgery. Maintenance therapy is only necessary for patients with symptomatic recurrent angioedema or related abdominal pain.

The anabolic steroids stanozolol View drug information or danazol View drug information are the treatment of choice for most patients. Virilizing side effects may occur even at the low doses needed for long-term maintenance. Regular monitoring for hepatic inflammation and adenomas is essential. Tranexamic acid View drug information may be used for maintenance but is contraindicated by a history of thrombosis. The manufacturer recommends regular eye examinations and liver function tests during long-term treatment of hereditary angioedema. ε-Aminocaproic acid (EACA) has also been used in some patients. Hereditary angioedema may be induced or exacerbated by estrogen in oral contraceptive pills which are relatively contra-indicated.

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Most patients with chronic urticaria can expect to benefit from treatment, but the prognosis for complete recovery has probably changed little from that in a survey done over 30 years ago, which identified that 50% of patients attending a tertiary referral center with urticaria alone were clear within a year, but that 20% with urticaria and angioedema continued to have symptoms 20 years from the time of onset 52.


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