Management of Urticaria: A Consensus Report

Torsten Zuberbier, Malcolm W. Greaves,*1 Lennart Juhlin,²1 Hans Merk,³1 Georg Stingl,§1 andBeate M. HenzDepartment of Dermatology and Allergy, ChariteÂ, Humboldt University Berlin, Germany; *St John's Institute of Dermatology, St Thomas's Hospital,

London, U.K.; ²Department of Dermatology, University Hospital, Uppsala, Sweden; ³Department of Dermatology, University Rheinland-Westfalen,

Aachen, Germany; §Department of Dermatology, General Hospital Vienna, Vienna, Austria

This consensus report is the result of a panel discus-sion during the International Clinically OrientedESDR Symposium Urticaria 2000. Urticaria has a pro-found impact on the quality of life and effectivetreatment is required. The most important are non-sedating H1 antihistamines. They have been provento be effective in double-blind controlled studies, butconcentrations higher than those recommended maybe necessary. Due to different urticaria subtypes and

the individual variation in the course of the diseaseand response to treatment, however, alternativetherapies may be required. Immunosuppressivedrugs like cyclosporine A and corticosteroids shouldnot be used long term due to undesirable side-effects. Key words: antihistamine/treatment/wheal.Journal of Investigative Dermatology SymposiumProceedings 6:128±131, 2001

This consensus report is the result of a panel discussionduring the International Clinically Oriented ESDRSymposium ``Urticaria 2000''. With over 100 partici-pants specializing in the ®eld of urticaria from morethan 15 countries, this consensus includes any possible

regional differences in therapeutic approach.Although urticaria is elicited by a great diversity of factors and

clinically presents in a highly variable way, its treatment follows thesame principles. The therapy of urticaria is best subdivided intothree basic lines of approach that should be followed in eachpatient. These are described below.

Avoidance or elimination of the eliciting stimulus Thisapproach is the most desirable because it is curative, but it isunfortunately not applicable in the majority of patients as the exacteliciting stimulus is frequently unknown. It can, however, beinstituted for the rare patients with IgE-mediated urticaria and forall patients with physical urticaria. In the latter group the impact ofphysical stimuli can be diminished and symptoms ameliorated byappropriate measures (e.g., cushioning in pressure urticaria). Inchronic urticaria treatment of associated in¯ammatory processes,including parasitic diseases and cancer, or of food and drugintolerance can be curative or at least helpful.

Inhibition of mast cell mediator release The next approachshould be aimed at the mast cell as the central effector cell.Unfortunately, there are only a few effective drugs available toinhibit mast cell mediator release.

Therapy of target tissues of mast cell mediators Currently,the most frequently used therapy aims to inhibit the effect of mastcell mediators on the target tissue and thus at the amelioration orsuppression of symptoms.

The speci®c treatment options in these three categories arediscussed in detail below.

ELICITING STIMULI

With this therapeutic approach, an exact diagnosis is a basicprerequisite. If remission on elimination or avoidance of thesuspected agent occurs, recurrence of symptoms on re-exposureprovides more proof of its causative nature as spontaneousremission of urticaria might also occur incidentally on eliminationof a suspected cause.

Drugs When such agents are suspected in the course of diagnosis,they should be omitted entirely or substituted by another class ofagents if indispensable. Drugs causing pseudoallergic reactions(prototype being aspirin) cannot only elicit but also aggravate pre-existing chronic urticaria (WuÈthrich, 1993), so that elimination willonly improve symptoms.

Physical stimuli Avoidance of physical stimuli for the treat-ment of physical urticaria would appear to be simple. Detailedinformation about the physical properties of the respective stimulusshould make the patient suf®ciently knowledgeable to recognizeand control his exposure in normal daily life. Thus, it is importantin dermographic urticaria as well as in delayed pressure urticaria topoint out that pressure is de®ned as force per area and that simpledevices (such as broadening of the handle of heavy bags) mayalready be helpful in the prevention of symptoms. Similarconsiderations hold for cold urticaria. Here the impact of thechill factor in cold winds needs to be remembered. For solarurticaria, the exact identi®cation of the range of elicitingwavelengths may be important for the appropriate selection ofsunscreens or for the selection of light bulbs with a UVA ®lter;however, in many patients the threshold for the individual elicitingstimulus is low and thus the total avoidance of symptoms is virtuallyimpossible.

Removal of infectious agents and treatment of in¯amma-tory processes In contrast to physical urticaria where coexisting,potentially disease-sustaining factors are only found in cold and

1087-0024/01/$15.00 ´ Copyright # 2001 by The Society for Investigative Dermatology, Inc.

128

Manuscript received June 19, 2001; accepted for publication June 19,2001.

Reprint requests to: Prof. T. Zuberbier, Department of Dermatologyand Allergy, Charite Campus Mitte, Schumannstr. 20/21, D-10117 Berlin,Germany. Email: torsten.zuberbier@charite.de

1Participated equally in writing this consensus report.

dermographic urticaria, chronic urticaria is often associated with avariety of in¯ammatory or infectious processes. This is regarded assigni®cant in some instances. These infections include those of thegastrointestinal tract like Helicobacter pylori (Wedi and Kapp, 1999)or bacterial infections of the nasopharynx, which should be treatedappropriately. Parasites, a rare cause of urticaria in industrialcountries, should be eliminated (Henz and Zuberbier, 1998). In thepast intestinal candidosis has been regarded as a highly importanteliciting factor for chronic urticaria (Champion et al, 1969), butrecent ®ndings fail to support a signi®cant causative role (Zuberbieret al, 1995). Nevertheless, it is recommended that massivecandidosis should be treated.

Apart from infectious diseases, chronic in¯ammatory processesdue to other diverse diseases have been identi®ed as causative forurticaria in the recent past. This holds particularly for gastritis,re¯ux esophagitis, or in¯ammation of the bile duct or bile gland(Bruno et al, 1998, pp 85±89; Zuberbier et al, 1995).

Removal of FceRI autoantibodies There are currently fewreported studies on the treatment of chronic urticaria by removingautoantibodies. Plasmapheresis has been shown to be of temporarybene®t in individual, severely affected patients (Grattan et al, 1992;Greaves, 2000). Alternatively, immunologic treatment with agentsinhibiting antibody formation as one of their actions, e.g.,cyclosporine (Fradin et al, 1991; Barlow et al, 1993; Toubi et al,1997; Grattan et al, 2000), or with high-concentration immuno-globulin infusions (O'Donnell et al, 1998) has been proven to behelpful. Due to the high cost, these therapies should be reserved forautoantibody-positive chronic urticaria patients unresponsive toother forms of treatment.

Dietary management IgE-mediated food allergy is rare inurticaria (Juhlin, 1981; Zuberbier et al, 1995). If identi®ed, thespeci®c food allergens need to be omitted as far as possible. In asubgroup of chronic urticaria patients pseudoallergic reactions tonaturally occurring food ingredients and in some cases to foodadditives are seen (Juhlin, 1981; Zuberbier et al, 1995; Pfrommeret al, 1996; Pigatto and Valsecchi, 2000). In these cases a dietcontaining only low levels of natural as well as arti®cial foodpseudoallergens should be instituted and maintained for aprolonged period of at least 3±6 mo. During this timespontaneous remission is achieved in approximately 50% ofpatients. It should be underlined that avoidance of type Iallergens clears urticaria symptoms within 24±48 h if relevantallergens are rapidly eliminated, whereas in pseudoallergy a diet hasoften to be maintained for 2±3 wk before bene®cial effects can beobserved.

MAST CELL DIRECTED THERAPY

At present, the most ef®cient drugs inhibiting mast cell mediatorrelease are corticosteriods. They should be avoided for long-termtreatment of chronic urticaria, as dosages necessary to suppresssymptoms are usually high with signi®cant side-effects. For acuteurticaria, however, a short course of corticosteroids may be helpfulin reducing disease duration (Zuberbier et al, 1996a). CyclosporineA also has a moderate, direct effect on mast cell mediator release(Stellato et al, 1992), but this drug cannot be recommended as astandard treatment due to potentially severe adverse effects.

PUVA reduces the numbers of mast cells in the upper dermis. Ithas been successfully used in mastocytosis and is helpful intreatment-resistant patients with this condition (Godt et al, 1997;Horio, 2000). For the treatment of chronic urticaria, UVA andUVB treatment for 1±3 mo can be added to the antihistaminetreatment (Hannuksela and Kokkonen, 1985; Olafsson et al, 1986).

Tolerance induction may also be considered under the headingmast cell directed therapy. This is sometimes used for cold urticariaand cholinergic urticaria therapy and as a standard treatment forsolar urticaria where even a rush therapy with UVA has beenproven to be effective within 3 d (Beissert et al, 2000).

THERAPY AT THE TARGET ORGAN

Nearly all symptoms of urticaria are mediated by H1-receptors. H1-receptor antagonists are thus of eminent importance in thetreatment of urticaria. With the increased availability of thisgroup of substances since the 1950s, urticaria has become one of thediseases that can be treated effectively with a very low adverse effectpro®le. The development of second-generation nonsedating orlow-sedating antihistamines has improved the quality of life ofurticaria patients. New generation antihistamines also exert anti-in¯ammatory effects such as cytokine release from basophils andmast cells (Lippert et al, 1995, 2000). This may be of additionalbene®t in controlling symptoms in urticaria if these effects occur ata clinically relevant dosage (Merk et al, 1985). There are somestudies that show the bene®t of a higher concentration ofantihistamines in individual patients (Kontou-Fili et al, 1989;Zuberbier et al, 1996b), but further investigations in this ®eld arenecessary. The possibility of increased adverse cardiac effects,especially with terfenadine and astemizole (Lindquist and Edwards,1997), is a consideration in the choice of the speci®c antihistamine,especially when using higher concentrations than those recom-mended by the manufacturers. Further progress with regard to drugsafety was achieved by the development of the antihistaminescetirizine, fexofenadine, and descarboxyloratadine, which arecytochrome P450-independent metabolites of earlier antihista-mines. The highest reported accidental overdose of antihistamine(50-fold of the prescribed dose of cetirizine in an 18-mo-old boy)induced no adverse effects other than sleepiness (Ridout and Tariq,1997). The main drug interactions have been described untilrecently for sedating antihistamines in association with drugsaffecting the central nervous system like analgetics, hypnotics,sedatives, and mood elevating drugs, as well as alcohol. In addition,MAO inhibitors can prolong and intensify anticholinergic effects.Some modern antihistamines are also metabolized by cytochromeP450 enzymes (Renwick, 1999), and increased plasma levels areobserved when there is concomittant treatment with drugsemploying this enzyme system for metabolism such as ketoconazoleor erythromycin.

In summary, considering their good safety pro®le, second-generation antihistamines must be considered as ®rst line symp-tomatic treatment for urticaria.

FURTHER THERAPEUTIC POSSIBILITIES

Whereas antihistamines at higher concentrations will controlsymptoms in probably more than 95% of patients with urticaria,alternative treatments are needed for the remaining unresponsivepatients. Many of the alternatives are based on open trials or casereports. More recent approaches include leukotriene antagonists(Ellis, 1998; Berkun and Shalit, 2000), interferon (Czarnetzki et al,1994), or immunoglobulins (O'Donnell et al, 1998).

On the other hand some treatment alternatives formerlyproposed have been shown to be ineffective in double-blind,placebo-controlled studies and should no longer be used. Theseinclude tranexamic acid and sodium cromoglycate in chronicurticaria (Laurberg, 1977; Thormann et al, 1980), nifedipin indermographic urticaria (Lawlor et al, 1988), and colchicine andindomethacine in delayed pressure urticaria (Dover et al, 1988;Lawlor et al, 1989).

Table I summarizes the current standard drug treatment andalternatives in several subtypes of urticaria.

Because the severity of urticaria may ¯uctuate, and becausespontaneous remission may occur at any time, it is recommendedthat the necessity for continued or alternative drug treatmentshould be re-evaluated every 3±6 mo.

CONCLUSION

The quality of life in urticaria is severely affected and managementof the disease should therefore be prompt and with closecooperation between patient and physician. Due to the high

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variability of disease severity, an individual approach is necessary foreach patient. As a ®rst line, triggering factors should be avoided asfar as possible and any associated diseases should be treated. In themajority of patients, symptomatic pharmacologic treatment ispossible with new generation antihistamines, with a very lowadverse effect pro®le and good patient compliance. In rare,nonresponding patients higher concentrations and alternativemedication should be tried. Most of these, such as corticosteroidsor cyclosporine, should be reserved for severely affected patientsbecause of their unfavorable adverse effect pro®le.

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Table I. Treatment in urticaria

Type of urticaria Standard treatment Alternative treatment

a. acute urticaria nonsedating H1-antihistaminesa initially prednisolone, 50 mg per d for 3 db. chronic urticaria nonsedating H1-antihistaminesa Combination: dapsone and pentoxifyllin

± increase dosage if necessary Combination: H1 and H2-blockerCombination: H1-blocker and b-sympathomimetics (e.g., terbutaline)Combination: H1-blocker and psychotropic drugsTricyclic antidepressants (doxepin)Danazol (stanozolol)Leukotriene antagonistsSulfazalazineCorticosteroidsCyclosporine Aa

InterferonPUVAPlasmapheresisImmunoglobulins

c. physical urticaria always consider avoidance of stimuli1. dermographic urticaria nonsedating H1-antihistaminesa

± increase concentration if necessary2. delayed pressure urticaria high-concentration nonsedating

H1-antihistaminesashort-term corticosteroidstrial with penicillin, 3 3 1.2 Mil IU per d p.o., or

3. cold urticaria H1-antihistaminesa doxycyline 2 3 100 mg per d p.o. induction of physicaltolerance (cold bath)

4. solar urticariad. special types of urticaria

1. cholinergic urticaria

induction of physical tolerance(hardening with UV light)nonsedating H1-antihistaminesa

nonsedating H1-antihistaminesa

Danazol, stanzolol± increase concentration if necessary (only severe cases)

aEf®cacy proven by double-blind, placebo-controlled studies.

130 ZUBERBIER ET AL JID SYMPOSIUM PROCEEDINGS

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