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disease progression. Arch Dermatol2003;139:857–66.

5 Agar NS, Wedgeworth E, Crichton S et al.Survival outcomes and prognostic factors inmycosis fungoides/Sézary syndrome:validation of the revised InternationalSociety for Cutaneous Lymphomas/European Organisation for Research andTreatment of Cancer staging proposal. J ClinOncol 2010;28:4730–9.

6 Benton EC, Crichton S, Agar NS et al.Cutaneous Lymphoma InternationalPrognostic Index (CLIPI). Br J Dermatol2010;163 (Suppl 1):8–11.

7 Kaye FJ, Bunn PA Jr, Steinberg SM et al. Arandomized trial comparing combinationelectron-beam radiation and chemotherapywith topical therapy in the initial treatmentof mycosis fungoides. N Engl J Med 1989;321:1784–90.

8 Scarisbrick JJ, Taylor P, Holtick U et al.U.K. consensus statement on the use ofextracorporeal photopheresis for treatmentof cutaneous T-cell lymphoma and chronicgraft-versus-host disease. Br J Dermatol2008;158:659–78.

9 Duvic M, Donato M, Dabaja B et al. Totalskin electron beam and non-myeloablativeallogeneic hematopoietic stem-cell trans-plantation in advanced mycosis fungoidesand Sézary syndrome. J Clin Oncol2010;28:2365–72.

Address for correspondence: Dr C Duhovic, Clinical Fellow inDermatology, St John’s Institute ofDermatology, St Thomas’ Hospital,Lambeth Palace Road, London SE1 7EH.Email: chris_duhovic@hotmail.com

Clinical Medicine 2012, Vol 12, No 2: 164–7

Urticaria has been recognised as an ill-ness since the time of Hippocrates. It isa common disease with an estimatedlifetime prevalence of 20%.1 The term isderived from the stinging nettle, Urticadioica. Indeed, the lay term for urticariais nettle rash. At one end of the clinicalspectrum, urticaria can be brief, mildand no more than a nuisance. Whensevere, acute urticaria may merge withlife-threatening anaphylaxis. Chronicurticaria may cause severe quality of lifeimpairment comparable to ischaemicheart disease.2

There has been recent debate about theterminology and classification of the dis-ease. In the latest European consensus onurticaria,3 it is defined as a heterogeneousgroup of diseases (ie the urticarias) ratherthan a single entity. The semantics areunimportant but reflect the recognitionthat there are distinct clinical patterns withmore than one aetiology.

Definition

The urticarias are characterised by short-lived, superficial, itchy pale swellingswith a surrounding red flare (Fig1) thatbecome pink and flatten as they resolveover hours (wheals), and/or deep paleswellings of the subcutis and submucosathat may be painful rather than itchy andlast longer (angio-oedema) (Fig 2).Collectively, urticaria presents withwheals, angio-oedema or both.

Clive Grattan, consultant dermatologist, St

John’s Institute of Dermatology, Guy’s and

St Thomas’ Hospitals NHS Foundation

Trust & Norfolk and Norwich University

Hospital

The urticarias:

pathophysiology

and management

Fig 1. Wheals are superficial swellingswith pale centres surrounded initially by ared flare that flatten and become assingular before fading.

Fig 2. Angio-oedema of theupper eyelidshowing a deepswelling withoutchange of skincolour.

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Classification (Table 1)

Urticaria has historically been dividedinto acute and chronic disease, depen-dent on continuous disease duration.This is somewhat useful in that acuteurticaria tends to run its course overweeks, may be due to an allergic triggerand usually does not recur if it can beidentified and avoided. It is easily thecommonest presentation of urticariaand usually happens to young people,although ranges from infancy to old age.Urticaria becomes chronic if diseaseactivity continues for six weeks orlonger. In clinical practice, the situationis often not so tidy. Patients present withurticarial activity that may be active fora few weeks, settle for another few weeksor months, then unpredictably return towhat it was previously. The term acuteor chronic intermittent urticaria can beused to describe this fluctuating activity(depending on the duration of the

episodes). This degree of precision maynot be important in the clinic butshould be taken into account whendefining populations for researchstudies.

It used to be routine common practiceto qualify chronic urticaria as ‘idiopathic’ when no physical triggercould be identified. However, it hasbecome increasingly accepted thataround 30% of patients who would pre-viously have been labelled ‘idiopathic’have functional autoantibodies thatrelease histamine from healthy donorbasophils and mast cells in vitro.4 Theterm ‘autoimmune urticaria’ has beenascribed to this subgroup of patients,5

although the concept has not beenendorsed by all authorities. Studies areongoing to define a cluster of clinical,biochemical and immunological criteriathat can be used in daily practice todefine these patients.

Spontaneous

The clinical terms ‘ordinary’6 or ‘sponta-neous’3 are now preferred in Europe todescribe urticaria by its presentationrather than aetiology, since the latter canbe difficult to assign in routine clinicalpractice. ‘Ordinary’ refers to the patternof disease and ‘spontaneous’ to theunpredictability of the swellings, but bothterms can apply to the same group ofpatients.

Inducible

Importantly, the group of spontaneousurticaria is different from patients presenting with urticaria induced by anexternal physical stimulus or agent.These inducible urticarias are usuallychronic in their course and have differentclinical characteristics to spontaneousurticaria. Even though the trigger can bedemonstrated by simple provocationtests, their cause remains unknown.

Spontaneous and inducible urticariascan overlap but urticaria is usually pre-dominantly one form or the other.

Contact

The third clinical pattern is contacturticaria. It is elicited either by skin ormucosal contact with a substance thatinduces histamine release by an allergicor non-allergic mechanism, or frominjection of vasoactive mediators,including histamine. The nettle stingreaction is a good example of this.Contact urticaria to cosmetics, foods,plants and stings is common but little iswritten about it since the cause is usu-ally self-evident to patients who do notconsult the medical profession. Theserious side of allergic contact urticariais that it can progress to anaphylaxis inhighly sensitive subjects (eg latexallergy).

Differential diagnosis

The noun ‘urticaria’ describes a diseasebut the adjective ‘urticarial’ is used todescribe a rash. The latter may be drug-induced, vasculitic or one component of

© Royal College of Physicians, 2012. All rights reserved. 165

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Table 1. Classification of the urticarias and differential diagnosis.

Urticaria Classification

Spontaneous ● Acute: �6 weeks continuous disease activity

● Chronic: 6 weeks continuous disease activity

Inducible

Physical Mechanical:

● Symptomatic dermographism

● Delayed pressure urticaria

● Vibratory angio-oedema

Thermal:

● Cold contact urticaria

● Heat contact urticaria

Other ● Cholinergic urticaria (sweating induced by overheating or stress)

● Exercise-induced anaphylaxis

● Food and exercise-induced anaphylaxis

● Aquagenic urticaria

Contact ● Immunological (allergic)

● Non-immunological (non-allergic)

Differential diagnosis

Urticarial drug rashes

Urticarial vasculitis

Autoinflammatory Acquired:

syndromes ● Schnitzler’s syndrome

● Adult Still’s disease

Hereditary:

● cryopyrin-associated periodic syndrome

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a wider systemic illness such as anautoinflammatory syndrome. It iscommon for articles on urticaria toembrace urticarial eruptions within thespectrum of urticaria because they mayappear indistinguishable. The clinician’sskill is to be able to distinguish anurticarial illness from urticaria since thepathogenesis, management and prog-nosis are importantly different.

Pathogenesis

It is widely accepted that the cutaneousmast cell has a central role in urticaria.There is some evidence that peripheralblood basophils are relevant to thedelayed response of spontaneousurticarial wheals, and they provide auseful model for the investigation ofmast cell degranulating stimuli in vitro.Although preformed histamine isreleased from mast cells on degranula-tion, together with tryptase and somecytokines, the receptors for histamine areon post-capillary venules and C-fibrenerve endings. These become permeableto plasma and signal the sensation of itchin the central nervous system. Lesionalskin biopsies show an early, but notimmediate, influx of inflammatory cellsincluding neutrophils, eosinophils,basophils and undifferentiated T-cells.7

Eosinophils may degranulate mast cellsindirectly by release of major basic pro-

tein.8 A sustained release of histaminefrom influxed basophils with generationof cysteinyl leukotrienes (LTs) may pro-long the wheal response. However, theclinical importance of LTs is not certainsince not many patients with chronicspontaneous urticaria show a convincingresponse to anti-LTs.

The stimulus for mast cell degranula-tion may be immunological or non-immunological (Fig 3). Cross-linking oftwo or more adjacent allergen-specific

immunoglobulin (Ig) E molecules boundto the high affinity IgE receptor (Fc�RI) onmast cells or basophils will initiate a seriesof calcium-dependent intracellular sig-nalling events leading to incompletedegranulation in allergic urticaria.Autoantibodies against IgE,9 Fc�RI10 orboth on basophils and mast cells11 causehistamine release in vitro and are thoughtto underpin autoimmune urticaria. Thisprocess may be complement (C)-depen-dent and C5a itself is a potent degranu-lating agent in the laboratory. Fortunately,opiates such as codeine and morphine donot often cause urticaria despite theirwidespread use in medicine, even thoughthey are standard laboratory non-immunological degranulating stimuli.

How physical stimuli cause inducibleurticarias is unclear but some historicalevidence from passive transfer experi-ments suggests that IgE may be involved.There is evidence that cutaneous mastcells are generally more ‘releasable’ inchronic spontaneous urticaria to non-immunological stimulation with com-pound 48/80.12 In contrast, bloodbasophils are less responsive to theimmunological stimulus anti-IgE, thelatter recovering as the disease goes intospontaneous remission.13

Urticaria is a disease characterised by wheals, angioedema or both

Patients may have spontaneous or inducible urticaria; sometimes both

The mast cell plays a central role in most patterns of urticaria by releasing histaminewhich, in turn, acts on capillaries and cutaneous nerve endings to elicit the characteristicitchy red wheals

Functional autoantibodies against IgE and the high affinity IgE receptor on mast cellsand basophils may cause autoimmune urticaria but can not be assayed routinely

The management of urticaria is primarily the avoidance of aggravating or trigger factorsand taking H1 antihistamines.

Antihistamine-resistant cases may require treatment with a variety of second and thirdline therapies used off licence

Key points

KEY WORDS: urticarias, diagnosis, pathogenesis, angio-oedema

Fig 3. Schematic diagram of non-immunological and immunological mast celldegranulating stimuli. FccRI = high affinity immunoglobulin (Ig) receptor.

Non-immunological Immunological

Allergen

An�-lgE

An�-FccRlCytokines

Opiates

Neuropep�des

C5a

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Angio-oedema without wheals

Urticaria may present as angio-oedemawithout wheals in approximately 10% ofpatients.1 This is an important subgroupsince some of these patients will havehereditary angio-oedema. There isincreasing recognition that angio-oedemawithout wheals may be mast cell-depen-dent or -independent. The latter form ismediated by bradykinin and is usuallyconsidered a different disease.

The important message for cliniciansis that hereditary angio-oedema andother presentations of mast cell-inde-pendent angio-oedema should alwaysbe actively confirmed or excluded byappropriate assessment, includingrequests for C4 complement and C1esterase inhibitor assays on fresh bloodsamples.

Management

The management of urticaria is well cov-ered in consensus documents.6,14 Thebasic principles are to identify from thehistory aggravating factors for chronicspontaneous urticaria that could poten-tially be minimised or avoided by thepatient. These include local heat,clothing pressure, emotional stress, non-steroidal anti-inflammatory drug intakeand dietary pseudoallergens. The symp-toms of the disease are treated withH1 antihistamines until spontaneousremission occurs.

Unfortunately, a minority of patientswith more severe urticaria require addi-tional measures to control their disease,including higher doses of antihista-mines,15 second-line targeted treatmentsincluding oral corticosteroids or immunosuppressive drugs (egciclosporin,16 methotrexate17 ormycophenolate mofetil18). Because of thenatural history of spontaneous remissionin chronic urticaria, it is hard to be sureon the current incomplete evidence

whether these are disease-modifying orprimarily disease-suppressing therapies.Further study is needed.

Attention has focused recently onomalizumab (a chimeric monoclonalanti-IgE biologic) because of its strikingeffectiveness in both antihistamine-unresponsive spontaneous19 andinducible urticarias.20 Licensing studiesare ongoing.

References

1 Maurer M, Weller K, Bindslev-Jensen C et al. Unmet clinical needs in chronicspontaneous urticaria. A GA2LEN taskforce report. Allergy 2011;66:317–30.

2 O’Donnell BF, Lawlor F, Simpson J et al.The impact of chronic urticaria on thequality of life. Br J Dermatol1997;136:197–201.

3 Zuberbier T, Asero R, Bindslev-Jensen C et al. EAACI/GA(2)LEN/EDF/WAO guide-line: definition, classification and diagnosisof urticaria. Allergy 2009;64:1417–26.

4 Greaves M. Chronic urticaria. Review. JAllergy Clin Immunol 2000;105:664–72.

5 Grattan CE. Autoimmune urticaria.Review. Immunol Allergy Clin North Am2004;24:163–81.

6 Grattan CE, Humphreys F; BritishAssociation of Dermatologists TherapyGuidelines and Audit Subcommittee.Guidelines for evaluation and managementof urticaria in adults and children. Br JDermatol 2007;157:1116–23.

7 Ying S, Kikuchi Y, Meng Q et al. TH1/TH2cytokines and inflammatory cells in skinbiopsy specimens from patients withchronic idiopathic urticaria: comparisonwith the allergen-induced late-phase cuta-neous reaction. J Allergy Clin Immunol2002;109:694–700.

8 Puccetti A, Bason C, Simeoni S et al. Inchronic idiopathic urticaria autoantibodiesagainst Fc epsilonRII/CD23 induce hista-mine via eosinophil activation. Clin ExpAllergy 2005;35:1599–1607.

9 Grattan CE, Francis DM, Hide M, GreavesMW. Detection of circulating histaminereleasing autoantibodies with functionalproperties of anti-IgE in chronic urticaria.Clin Exp Allergy 1991;21:695–704.

10 Hide M, Francis DM, Grattan CE et al.Autoantibodies against the high-affinityIgE receptor as a cause of histamine release

in chronic urticaria. N Engl J Med1993;328:1599–604.

11 Niimi N, Francis DM, Kermani F et al.Dermal mast cell activation by autoanti-bodies against the high affinity IgEreceptor in chronic urticaria. J InvestDermatol 1996;106:1001–6.

12 Bédard PM, Brunet C, Pelletier G, Hébert J. Increased compound 48/80 induced localhistamine release from nonlesional skin ofpatients with chronic urticaria. J AllergyClin Immunol 1986;78:1121–5.

13 Eckman JA, Hamilton RG, Gober LM et al.Basophil phenotypes in chronic idiopathicurticaria in relation to disease activity andautoantibodies. J Invest Dermatol2008;128:1956–63.

14 Zuberbier T, Asero R, Bindslev-Jensen C et al. EAACI/GA(2)LEN/EDF/WAO guide-line: management of urticaria. Allergy2009;64:1427–43.

15 Staevska M, Popov TA, Kralimarkova T et al. The effectiveness of levocetirizine and desloratadine in up to 4 times conven-tional doses in difficult-to-treat urticaria.J Allergy Clin Immunol 2010;125:676–82.

16 Grattan CE, O’Donnell BF, Francis DM et al. Randomized double-blind study ofcyclosporin in chronic ‘idiopathic’urticaria. Br J Dermatol 2000;143:365–72.

17 Perez A, Woods A, Grattan CE.Methotrexate: a useful steroid-sparingagent in recalcitrant chronic urticaria. Br JDermatol 2010;162:191–4.

18 Shahar E, Bergman R, Guttman-Yassky E,Pollack S. Treatment of severe chronicidiopathic urticaria with oral mycopheno-late mofetil in patients not responding toantihistamines and/or corticosteroids. Int JDermatol 2006;45:1224–7.

19 Maurer M, Altrichter S, Bieber T et al.Efficacy and safety of omalizumab inpatients with chronic urticaria who exhibitIgE against thyroperoxidase. J Allergy ClinImmunol 2011;128:202–9.

20 Metz M, Altrichter S, Ardelean E et al.Anti-immunoglobulin E treatment ofpatients with recalcitrant physical urticaria.Int Arch Allergy Immunol 2011;154:177–80.

Address for correspondence: Dr CGrattan, Norfolk and NorwichUniversity Hospital, Colney, NorwichNR4 7UY.Email: clive.e.grattan@gstt.nhs.uk

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