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Keywords:

  • angioedema;
  • consensus;
  • diagnosis;
  • hives;
  • wheal

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. External review
  5. Funding
  6. Future updates of the guidelines
  7. Conflicts of interest
  8. References

This methods report describes the process of guideline development in detail. It is the result of a systematic literature review using the ‘Grading of Recommendations Assessment, Development and Evaluation’ (GRADE) methodology and a structured consensus conference held on 28 and 29 November 2012, in Berlin. It is a joint initiative of the Dermatology Section of the European Academy of Allergy and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS) and is published in Allergy 2014; 69:868–887.

Abbreviations
AAAAI

American Academy of Allergy, Asthma & Immunology2

AEDV

Spanish Academy of Dermatology and Venereology

ASBAI

Brazilian Association of Allergy and Immunopathology

CDA

Chinese Dermatologist Association

CSACI

Canadian Society of Allergy and Clinical Immunology

DDG

German Society of Dermatology

DGAKI

German Society of Allergology and Clinical Immunology

EAACI

European Academy of Allergology and Clinical Immunology

EDF

European Dermatology Forum

ESCD

European Society of Contact Dermatitis

GA2LEN

Global Allergy and Asthma European Network

IAACI

Israel Association of Allergy and Clinical Immunology

IADVL

Indian Association of Dermatologists, Venereologists and Leprologists

JDA

Japanese Dermatological Association

MSAI

Malaysian Society of Allergy and Immunology

ÖGDV

Austrian Society for Dermatology

SDF

French Society of Dermatology

SGDV

Swiss Society for Dermatology and Venereology

SPDV

Portuguese Society of Dermatology and Venereology

UNEV

Urticaria Network

WAO

World Allergy Organization

This methods report provides information on the development process of the 2013 revision and update of the European Academy of Allergology and Clinical Immunology (EAACI), Global Allergy and Asthma European Network (GA2LEN), European Dermatology Forum (EDF), and World Allergy Organization (WAO) guideline for the definition, classification, diagnosis, and management of urticaria. It is an update of the previous international guidelines on urticaria [1, 2].

The guideline update was developed in alignment with the quality criteria contained within the Appraisal of Guidelines Research & Evaluation (AGREE) Instrument, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group, and the German Association of Scientific Medical Societies (AWMF).

The update of the urticaria guidelines was made using a structured development process comprising a systematic search of the literature in the relevant databases, a systematic evaluation of the search results, and a consensus conference based on formal consensus methodology (structured consensus conference).

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. External review
  5. Funding
  6. Future updates of the guidelines
  7. Conflicts of interest
  8. References

Nomination of experts

In January 2012, GA2LEN started the updating process for the urticaria guidelines by contacting international and national societies for allergy and dermatology to explore whether they wanted to participate in the guideline revision and update process. The societies that committed to participate are listed in Table 1. Already the last version of this guideline was based on the involvement of GA2LEN, EAACI, and EDF in cooperation with European Academy of Dermatology and Venereology (EADV) and the WAO.

Table 1. Societies that participated in the 2013 update and revision of the urticaria guidelines
Societies involved in the Urticaria Guidelines 2013
  1. a

    See section on ‘External review’.

ÖGDV, Austrian Society for DermatologyEAACI, European Academy of Allergology and Clinical ImmunologyWAO, World Allergy OrganizationASBAI, Brazilian Association of Allergy and ImmunopathologyGA2LEN, Global Allergy and Asthma European NetworkAAAAI, American Academy of Allergy, Asthma & ImmunologyaIADVL, Indian Association of Dermatologists, Venereologists and Leprologists
CSACI, Canadian Society of Allergy and Clinical ImmunologyJDA, Japanese Dermatological AssociationDDG, German Society of DermatologyMSAI, Malaysian Society of Allergy and ImmunologySDF, French Society of DermatologySGDV, Swiss Society for Dermatology and VenereologyIAACI, Israel Association of Allergy and Clinical Immunology
EDF, European Dermatology ForumDGAKI, German Society of Allergology and Clinical ImmunologyCDA, Chinese Dermatologist AssociationUNEV, Urticaria NetworkSPDV, Portuguese Society of Dermatology and VenereologyESCD European Society of Contact DermatitisAEDV, Spanish Academy of Dermatology and Venereology

All participating societies were asked to name their delegates to the expert panel and authorship groups, taking into account that:

  1. delegates were allowed to represent more than one society and
  2. panel members and co-authors of the previous guideline were recommended to the societies as possible delegates.

As for the previous revision and update of urticaria guidelines, the consensus conference including the discussion and voting procedure was open to all experts interested in participating. Hence, the 2013 update and revision of the guideline is based on the contributions of the society-nominated expert panel members as well as on other experts interested. This ‘enlarged consensus group’ is believed to broaden the acceptance of the guidelines and helping their dissemination and implementation.

In addition, the consensus conference was attended by two chronic urticaria (CU) patients with good knowledge of the English language treated at the urticaria clinic of the Department of Dermatology and Allergy, Charité – Universitätsmedizin Berlin, as well as a delegate of the nonprofit patient interest organization UNEV (currently the only patient interest organization in the field of urticaria in Europe).

For a detailed overview of participants of the consensus conference, see Table 2.

Table 2. The experts nominated by the commissioning societies formed the steering committee
 NameCity/countryInstitution/companyDelegate of
  1. a

    See section on ‘External review’.

1Aberer, WernerGraz (Austria)Department of Dermatology, Medical University of Graz, Graz, AustriaÖGDV
2Asero, RiccardoMilano (Italy)Allergy Clinic, Clinica San Carlo, Paderno Dugnano (MI), ItalyEAACI
3Bindslev-Jensen, CarstenOdense (Denmark)Department of Dermatology and Allergy Centre, Odense University Hospital and University of Southern Denmark, Odense, DenmarkGA2LEN
4Brzoza, ZenonKatowice (Poland)Department of Internal Diseases, Allergology and Clinical Immunology in Katowice, Medical University of Silesia, PolandEAACI
5Canonica, Walter G.Genova (Italy)Respiratory Diseases & Allergy, University of Genoa, IRCCS AOU SanMartino, Genoa, ItalyWAO
6Church, MartinBerlin (Germany/UK)Department of Dermatology and Allergy, Allergy-Centre-Charité, Charité – University Hospital Berlin, Berlin, GermanyGA2LEN
7Cox, LindaDavie (FL, USA)Nova Southeastern University School of Osteopathic Medicine, DavieAAAAIa
8Ensina, Luis FelipeSão Paulo (Brasil)Federal University of Sao Paulo, Sao Paulo, BrazilASBAI
9Giménez-Arnau, AnaBarcelona (Spain)Hospital del Mar. Parc de Salut Mar, Universitat Autònoma Barcelona, SpainEAACI and AEDV,
10Godse, KiranMumbai (India)

Department of Dermatology, Dr. D. Y. Patil Medical College & Hospital, Nerul, Navi

Mumbai, India

IADVL
11Gonçalo, MargaridaCoimbra (Portugal)Clinic of Dermatology, Faculty of Medicine and University Hospital, Coimbra, PortugalSPDV and ESCD
12Grattan, CliveNorfolk (UK)St John's' Institute of Dermatology, Guy's' and St Thomas' Hospitals NHS Foundation Trust, UKEAACI
13Hébert, JaquesQuébec (Canada)Center for Applied Research on Allergy Québec, Québec, CanadaCSACI
14Hide, MichihiroHiroshima (Japan)Department of Dermatology, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, JapanJDA
15Kaplan, AllenCharleston (SC, USA)Department of Medicine, Division of Pulmonary and Critical Care Medicine, Allergy and Clinical Immunology, Medical University of South Carolina, Charleston, SC, USAWAO
16Kapp, AlexanderHannover (Germany)Department of Dermatology and Allergy, Hannover Medical School, Hannover, GermanyDDG
17Lang, DavidCleveland (OH, USA)Respiratory Institute, Cleveland ClinicAAAAIa
18Latiff, Abdul A.H.Kuala Lumpur (Malaysia)Department of Paediatrics, Pantai Hospital Kuala Lumpur, Bangsar, Kuala Lumpur, MalaysiaMSAI
19Mathelier-Fusade, PascaleParis (France)Department of Dermatology and Allergy, University Hospital of Tenon, Paris, FranceSDF
20Maurer, MarcusBerlin (Germany)Department of Dermatology and Allergy, Allergy-Centre-Charité, Charité – University Hospital Berlin, Berlin, GermanyEAACI
21Metz, MartinBerlin (Germany)Department of Dermatology and Allergy, Allergy- Centre- Charité, Cahrité – University Hospital Berlin, Berlin, Germany EAACI
22Nast, AlexanderBerlin (Germany)Department of Dermatology and Allergy, Allergy-Centre-Charité, Charité – University Hospital Berlin, Berlin, GermanyModerator
23Saini, SarbjitBaltimore (USA)Johns Hopkins Asthma and Allergy Center, Baltimore (MD), USAAAAAI and WAO
24Sánchez-Borges, MarioCaracas (Venezuela)Allergy and Clinical Immunology Department Centro Médico-Docente La Trinidad, Caracas, VenezuelaWAO
25Schmid-Grendelmeier, PeterZürich (Switzerland)Allergy Unit, Department of Dermatology, University Hospital, Zürich, SwitzerlandSGDV
26Simons, EstelleManitoba (Canada)Department of Pediatrics & Child Health, Department of Immunology, University of Manitoba, CanadaCSACI
27Staubach, PetraMainz (Germany)Department of Dermatology, University Medical Center Mainz, GermanyUNEV
28Sussman, GordonToronto (Canada)Division of Allergy and Clinical Immunology, University of Toronto, Toronto (ON), CanadaCSACI
29Toubi, EliasHaifa (Israel)Bnai-Zion Medical Center, Faculty of Medicine, Technion, Haifa, IsraelIAACI
30Vena, GinoBari (Italy)Unit of Dermatology and Venereology, Department of Biomedical Sciences and Human Oncology, University of Bari, Bari, ItalyEDF
31Wedi, BettinaHannover (Germany)Department of Dermatology and Allergy, Hannover Medical School, Hannover, GermanyDGAKI
32Zhu, XuejunBeijing (China)Department of Dermatology, Peking University First Hospital, Beijing, ChinaCDA
33Zuberbier, TorstenBerlin (Germany)Department of Dermatology and Allergy, Allergy-Centre-Charité, Charité – University Hospital Berlin, Berlin, GermanyEDF and GA2LEN

Selection of relevant key questions to be addressed during the update and revision process of the guideline

Prior to the consensus meeting, a list of questions was developed by the expert panel's steering committee (Zuberbier, Maurer, Nast; Berlin) based on the previous guidelines. This list of questions was circulated among all panel members for review. They were then rated with respect to their importance, and a final selection was prepared by the steering committee and agreed upon by the expert panel.

Check for existing guidelines and systematic reviews

The update and revision of the guidelines was based on three previous versions of the guidelines, which resulted from urticaria guideline consensus conferences in 2000, 2004, and 2008 [1-6]. Other guidelines were not systematically assessed. Reasons were limited resources and the fact that the previous versions were the most suitable basis for the development of the 2013 guideline.

Literature search and update based on existing systematic reviews

The formalized literature research performed entailed:

  1. the previous versions of the guidelines [1-6]. For the previous versions of the guideline, a systematic search as described in the respective publications had been conducted and all randomized trials published up to and in 2008 had been evaluated and documented in GRADE tables.
  2. a new literature search for all publications as of 2008.

To find relevant trials, we performed systematic searches of the databases MEDLINE and EMBASE (for search strategies, see Table 3) and hand-searches of abstracts at international allergy congresses between 2008 and 2012. Search date was February 22, 2012, assessed via OVID.

Table 3. Search strategies
Suche vom 22.02.2012
1. exp Angioedema/
2. “angioedema*”.ti.
3. “angiooedema*”.ti.
4. “quincke* edema*”.ti.
5. “quincke* oedema*”.ti.
6. “angioneuro* edema*”.ti.
7. “angioneuro* oedema*”.ti.
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. exp Urticaria/
10. “urticaria*”.ti.
11. “hives*”.ti.
12. 9 or 10 or 11
13. 8 or 12
14. limit 13 to (yr=“2009 -Current” and (english or german))

Urtikaria_Medline in Process

Suche vom 22.02.2012

1. “angioedema*”.ti.
2. “angiooedema*”.ti.
3. “quincke* edema*”.ti.
4. “quincke* oedema*”.ti.
5. “angioneuro* edema*”.ti.
6. “angioneuro* oedema*”.ti.
7. 1 or 2 or 3 or 4 or 5 or 6
8. “urticaria*”.ti.
9. “hives*”.ti.
10. 8 or 9
11. 7 or 10
12. limit 11 to (yr=“2009 -Current” and (english or german))

Urtikaria_Embase

Suche vom 22.02.2012

1. *angioneurotic edema/
2. “angioedema*”.ti.
3. “angiooedema*”.ti.
4. “quincke* edema*”.ti.
5. “quincke* oedema*”.ti.
6. “angioneuro* edema*”.ti.
7. “angioneuro* oedema*”.ti.
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. *urticaria/
10. “urticaria*”.ti.
11. “hives*”.ti.
12. 9 or 10 or 11
13. 8 or 12
14. limit 13 to ((english or german) and yr=“2009 -Current”)

Urtikaria_Cochrane

Suche vom 22.02.2012

1. exp Angioedema/
2. “angioedema*”.ti.
3. “angiooedema*”.ti.
4. “quincke* edema*”.ti.
5. “quincke* oedema*”.ti.
6. “angioneuro* edema*”.ti.
7. “angioneuro* oedema*”.ti.
8. 1 or 2 or 3 or 4 or 5 or 6 or 7
9. exp Urticaria/
10. “urticaria*”.ti.
11. “hives*”.ti.
12. 9 or 10 or 11
13. 8 or 12
14. limit 13 to (yr=“2009 -Current” and (english or german))

The results were then screened, evaluated, and included or excluded by two (in some cases three) assessors (Maurer, Metz, and/or Zuberbier). The bibliographic information was then transferred to an EndNote database, and the full texts were obtained if available.

Standardized inclusion/exclusion and data extraction

Identified literature was evaluated by two of the assessors (Maurer and Zuberbier). The data generated were compared with each other; any discrepancies were reviewed by a third assessor (Metz) and finally resolved through discussion.

Literature had to fulfill specific criteria in order to be included into the guideline:

  1. direct relevance to the specific issue.
  2. no serious methodological limitations in the study with respect to the quality of the information for the selected outcome as determined by the assessors.

The included literature was selected with respect to their hierarchy in the ‘evidence pyramid’, for example if a good systematic review was available and up to date no further systematic analysis of randomized controlled trials (RCTs) or cohort studies was carried out. This was chosen in case of existing high-quality RCTs; no further systematic analysis of cases series or case reports was carried out.

Use of the GRADE system and grading of evidence

In the previous version of the guideline, studies were evaluated using the GRADE approach. The key principle of this approach is to provide transparency as well as clear and explicit criteria for assessing the quality of evidence and for grading the strength of recommendations [7] based on risk vs benefits. The strength of a recommendation and the quality of supporting evidence were assessed independently for each recommendation, taking into consideration negative and positive effects such as side-effects, reduction of urticaria symptoms, practicability, feasibility, and costs.

Importantly, the GRADE system permits strong recommendations supported by low- or, very rarely, very low-quality evidence from downgraded RCTs or observational studies. On the other hand, weak recommendations may be based on high-quality evidence if other factors are important, for example the price of a treatment option.

The phrase ‘we recommend’ was used for strong recommendations and ‘we suggest’ for weak recommendations in order to adhere to the same methodology used for the Allergic Rhinitis and its Impact on Asthma Guideline 2008 update [8].

Consensus conference

The structured consensus conference ‘URTICARIA 2012’ took place in Berlin, Germany, on November 28/29, 2012. The conference was supervised by PD Dr Alexander Nast, who is a certified guideline advisor and moderator of the AWMF. During the conference, updates on the scientific knowledge in the field of urticaria were presented in short, focused presentations by panel members. This was followed by two interactive sessions, one dedicated to the nomenclature, classification, and diagnostic algorithm in urticaria and the other to its treatment. During these sessions, the recommendations prepared by the panel members were presented to the participants and voted on.

Voting was done with the use of red and green voting cards and performed in a structured way. Only ‘yes’ or ‘no’ voting was allowed in order to ensure clear majority decisions. If a recommendation did not achieve 90% agreement during the first voting, the respective recommendation was re-discussed and, if needed, rephrased. In order to pass in the second voting round, a minimum of >75% agreement had to be achieved.

Under headline 3.2, all the preselected questions were addressed and under 3.4 the corresponding recommendations are listed as well as the protocol of the different alternatives, which were discussed and voted on during the consensus meeting.

External review

The guidelines underwent an extensive external review. From March 26, 2013, until April 26, 2013, the guideline was reviewed and finally endorsed by the participating societies.

During this review process, societies were granted to make amendments only limited to scientific errors. This regulation was a consequence of the voting rules agreed upon for the process developing the guideline.

Specifically, the wording of the recommendations had to remain unchanged during the review process. The recommendations are ultimately a result of several perspectives, involving the votes of the panel members delegated by the societies, as well as additional opinions that were taken into consideration during the consensus meeting: practicing physicians in urticaria as well as affected patients.

However, all societies involved had the possibility to not endorse the guideline upon review or to provide additional comments regarding aspects and conditions specific to their countries or geographic region.

The AAAAI made the decision not to endorse the guideline as they felt there were too many differences to an US Urticaria Practice Parameter under development. The AAAAI therefore decided to define their contribution to the guideline as ‘with participation of the American Academy’, but not as an endorsing founder society.

Other participants

The consensus conference ‘URTICARIA 2012’ including the discussion and voting process was open to all experts interested in participating. Hence, the 2013 guidelines resulted from discussions and a consensus by delegates nominated by scientific societies as well as other experts (Table 4).

Table 4. Additional members of the consensus group
Last nameFirst nameCountry code
AbajianMarinaDE
Al AhmadMonaKW
AltrichterSabineDE
ArdeleanElenaDE
AsoyanArmenakRU
Balaña VilanovaMontserratES
BalpMaria-MagdalenaCH
BarryKayUK
Bech-ThomsenNielsDK
Ben HamidaAmnaLB
BkovPer StahlDK
Boccon-GibodIsabelleFR
BonnekohHannaDE
BoonpiyathadSawadTH
BräutigamMatthiasDE
BroomBrianNZ
BrugginkT.I.M.NL
BrzostekDorotaPL
BubolicSuzyCA
BukovskisMarisLV
Burum-AuensenEspenNO
CamposRegisBR
CasanovasMireiaES
CassanoNicolettaIT
Chapman-RotheNadineDE
ChenHongCN
ChenYueCN
ChiriacAncaRO
ChiriacAncaRO
ChomicieneAnzelikaLT
CruzAna TeresaPT
CurtoLaiaES
Czarnecka-OperaczMagdalenaPL
DahlbornAnna-KarinSE
DanilychevaInnaRU
DaschnerAlvaroES
DibraMarinelaAL
DicksonMarionUK
DiengMame ThiernoSN
DiengSouleymaneCI
DouladirisNikolaosGR
DrobikOlgaRU
El AmineMiladCI
EnevoldsenHenriette KøhlerDK
FalkencroneSidselDK
FangHongCN
Ferrer PugaMartaES
FieldsStephenCA
FigliomeniMariaUS
FitzGibbonJoeIE
FitzharrisPennyNZ
FominaDariaRU
FordJulieCH
FrambachYvonneDE
FrølundLarsDK
FucciVirginiaIT
GalloRosellaIT
GaoGuangchengCN
GarciaRobertoUS
GeorgiouPanayiotisUK
GerickeJanineDE
GigauriTinatinGE
GoryachkinaLyudmilaRU
GoujonCatherineFR
GreavesMalcolmUK
GroffikAdrianeDE
HaoFeiCN
HawroTomaszDE
HeibergJensDK
HermesBarbaraDE
HerwigEddaDE
HotingEdoDE
HoustonParulCH
HullerElkeDE
IlharcoAnaPT
Isidoro GarciaOlgaES
IzquierdoIñakiES
JakobThiloDE
JentzschClaudiaDE
JohannsenHenningAU
Jun YoungLeeKR
KaraulovAlexanderRU
KiechleTamaraCH
KinaciyanTamarAT
KnolEdwardNL
KoberAnitaSE
KorczynskaPaulinaPL
KorolevaMariaRU
KotiIoannaDE
KowalskiMarekPL
KraasLuiseDE
KrajnyMilosCA
KrauseKarolineDE
KresselGabyDE
KruszewskiJerzyPL
KuhnChristofCH
KurzawaRyszardPL
LandroLinnNO
LangeDirkDE
LawlorFrancesUK
LecocqBrigitteFR
LeruPollianaRO
LeslieTabiUK
LiChengxinCN
LiLinfengCN
LippertUndineDE
LiverisAndreasCY
MagerlMarkusDE
MaggiEnricoIT
MahlerVeraDE
MakrisMichaelGR
MarroucheNadineUK
MarslandAlexanderUK
MartineLefebvreBE
Martinez-EscalaM.-EstelaES
Mathelier-FusadePascaleFR
MaurerMarcusDE
MerkHansDE
MetzMartinDE
MillingtonGeorgeUK
MłynekAgnieszkaDE
MobackenHåkanSE
MöckelAndyDE
MokronosovaMarinaRU
NakonechnaAllaUK
NastAlexanderDE
NosbaumAudreyFR
OhanyanTatevikDE
PawliczakRafałPL
PelckIngerDK
PereiraCatarinaPT
PigattoPaolo Daniele MariaIT
PopescuFlorin DanRO
PreiszPaulAU
RedlinAndreasDE
ReiterNadineDE
RessKristaEE
RoduitCarolineCH
RogalaBarbaraPL
RöhrbeinJanDE
RomanoAntonino GaetanoIT
RosenKarinUS
RupnikHelenaSI
SainiSarbjitUS
Sánchez-BorgesMarioVE
Santamaria MasdeuEvaES
Santa-MartaCristinaPT
SaraivaTaniaPT
ScarupaMarkUS
ScerriLawrenceMT
Schmid-GrendelmeierPeterCH
SchoepkeNicoleDE
SchwabKatharinaDE
SieC.L.NL
SiebenhaarFrankDE
SilvaBarbaraBR
Silvestre SalvadorJuan FranciscoES
SlabyKatarzynaPL
SmeetsSergeNL
SpiewakRadoslawPL
SpohrAdrianDE
StasiiEcaterinaMD
StockmanAnneliesBE
SzepietowskiJacekPL
Tarrago TilloJavierES
TedeschiDonatellaIT
Tempels-PavlicaZanaNL
ThielenAntjeDE
TreudlerReginaDE
TsakonaChrysUK
TumeleroMelissaBR
van DalenG.NL
VardanyanKarinaRU
Veleiro PerezBeatrizES
Vella BriffaDomenicMT
VestergaardChristianDK
WagnerNicolaDE
Weber-ArdenJuliaDE
WellerKarstenDE
WieczorekDorotheaDE
YongAdrianUK
ZazzaliJamesUS
ZhangJianzhongCN
ZuotaoZhaoCN

Selection of relevant interventions and key questions

The following questions were suggested and considered relevant to be answered by the guideline. Depending on feasibility, they were answered on an evidence-based or on a consensus-based/good clinical practice level. For every sentence, it is clearly stated whether the recommendation is given based on ‘clinical practice’ or whether a ‘level of evidence’ is provided.

  1. Should the current classification be maintained in urticaria?
  2. Should the current activity score (UAS7) be maintained assessing severity in urticaria?
  3. Should routine diagnostic measures be performed in acute urticaria?
  4. Should routine diagnostic measures be performed in chronic spontaneous urticaria (CSU)?
  5. Should extended diagnostic measures be performed in CSU?
  6. Should routine diagnostic measures be performed in inducible, nonspontaneous subtypes of urticaria?
  7. Which instrument should be used to measure quality of life (QoL) in urticaria?
  8. Should patients with an allergic sensitization (positive specific IgE/skin prick test) avoid certain food items?
  9. Should treatment aim at complete symptom control in urticaria?
  10. Are modern second-generation H1-antihistamines (AHs) to be preferred over first-generation H1-AHs in the treatment of urticaria?
  11. Are modern second-generation AHs as first-line treatment in urticaria to be preferred against other licensed medication?
  12. Is an increase in the dose to fourfold of modern second-generation H1-AHs useful as second-line treatment and to be preferred over other treatments in urticaria?
  13. Are H2-AHs useful in the treatment of urticaria as third-line therapy?
  14. Is cyclosporin A useful as add-on treatment in patients unresponsive to high doses of H1-AHs as third-line treatment?
  15. Is omalizumab (OMA) useful in the treatment of patients unresponsive to high doses of H1-AHs as third-line treatment?
  16. Should oral corticosteroids be used in the treatment of urticaria?
  17. Should leukotriene antagonists be used in the third-line treatment of urticaria?
  18. Is dapsone useful in the treatment of urticaria as third-line therapy?
  19. Should the same treatment algorithm be used in children?
  20. Should the same treatment algorithm be used in pregnant women and during lactation?
  21. Are pseudoallergen-free diets useful in the extended diagnostic program of CSU?
  22. Should modern second-generation AHs be taken regularly or as needed?
  23. Should different H1-AHs be used at the same time?
  24. If there is no improvement, should higher than fourfold doses of H1-AHs be used?

Systematic literature search

The systematic search identified 2804 hits in all databases, and after checking for doubles, 1956 hits remained for abstract screening (see Table 5).

Table 5. Hits in systematic literature search
 AllDoubles excluded
MEDLINE815793
MEDLINE in Process170168
EMBASE1771978
Cochrane Library4817
Total28041956

After abstract screening, 188 full texts were obtained, and from these, 67 were included into the body of evidence for the new guidelines.

Consensus conference and voting results

Should the current classification be maintained in urticaria?

We recommend the use of this version of the classification of the 2013 guideline revision (strong recommendation/clinical consensus, accepted with 100%).

Reasoning/summary from discussion

The current classification was proposed for the first time in the 2008 revision and update of the urticaria guideline [1] and has been adopted by multiple national or regional guidelines. Furthermore, the classification has been adhered to in all trials published since then and in the vast majority of publications. In addition, the current classification, which explicitly omits the term ‘chronic idiopathic urticaria’, has been used in regulatory documents. Based on this, we recommend the continued use of this updated version of the classification. Inducible urticaria subtypes are chronic diseases as well but as in many other allergic diseases, symptoms depend on the presence of the trigger.

See Supporting Evidence in Table 6.

Table 6.  
Investigated studyStudy designP-value outcomeLimitationsInconsistency, indirectness, imprecisionQualityImportanceYearCitation
  1. n.a., not applicable.

 S3 level guidelinen.a.None HighHigh2009Zuberbier et al. [2]
Should the current UAS7 be maintained assessing severity in urticaria?

We recommend the use of UAS7 to assess severity (strong recommendation/clinical consensus, accepted with 100%).

Reasoning/summary from discussion

The UAS7 is a validated tool for assessing disease activity in CSU and was already recommended to be used in routine clinical practice and clinical trials in the previous guideline. Recently another score, the Urticaria Severity Score (USS), has been developed and validated [9]. The USS combines assessment of signs and symptoms with QoL questions. The UAS7, however, remains the recommended gold standard for assessing activity (strong recommendation/high-quality evidence). It should be used as originally established, without modification (i.e., once daily per patient recording of wheal numbers (no wheals: score value = 0, 1–20 wheals: score value = 1, 21–50 wheals: score value = 2, >50 wheals: score value = 3, no pruritus: score value = 0, mild pruritus: score value = 1, moderate pruritus: score value = 2, strong pruritus: score value = 3)). The use of the original UAS7 ensures the comparability of previous and new trials, because the UAS7 has been used in the majority of trials published during the last 5 years. To ensure the future comparability of new trials, we recommend adherence to the currently proposed UAS7 (strong recommendation/high-quality evidence) in clinical trials. This decision is not based on inferiority of the USS to the UAS7 score as head-to-head investigations are missing. Reasons are practical considerations: UAS7 is now established and changing it would not allow comparison of future trials with older ones. Both scores may be employed by physicians in daily practice.

See Supporting Evidence in Table 7.

Table 7.  
Investigated studyStudy designP-value outcomeLimitationsQualityImportanceYear
  1. n.a., not applicable; QoL, quality of life.

Jariwala, Moday [9]Prospectiven.a.Validated in 80 patients, single center onlyHighHigh2009
Mlynek, Zalewska-Janowska [10]ProspectiveP = 0.05 correlated later with QoLValidated in three patients, single centerHighHigh2008
Should routine diagnostic measures be performed in acute urticaria?

We recommend against routine diagnostic measures in acute urticaria (strong recommendation/clinical consensus, accepted with 100%).

Reasoning/summary from discussion

Acute urticaria in more than 95% of the cases is self-limited and it usually has a duration of <2 weeks. In addition, acute urticaria can generally be treated satisfactorily with AHs and it is frequently associated with upper respiratory tract viral infections where no clinical consequence would follow from determining the specific virus. Based on these facts, the previous version of the guideline recommended that no routine diagnostic measures be performed in acute urticaria except in the case of a clear suspicion from the patient history of an eliciting agent. Since the last guideline, no systematic reviews or trials have been published showing a reasonable cost/benefit ratio of routine diagnostics in acute urticaria. We recommend not using routine diagnostic measures in acute urticaria except in the case of a suspicion clearly derived from the patient history for an eliciting agent. This decision is based mainly on a negative cost/benefit ratio.

See Supporting Evidence in Table 8.

Table 8.  
Investigated studyStudy designP-value outcomeLimitationsQualityImportanceYear
  1. n.a., not applicable.

Zuberbier, Ifflander [11]Prospective, open, monocentric, observational studying course of untreated firstly diagnosed acute urticaria under 2 forms of standard treatmentn.aOld study which was never repeated, high rate of spontaneous remission reflects clinical experience of all consensus participantsLowHigh1996
Should routine diagnostic measures be performed in CSU?

We recommend for only very limited routine diagnostic measures in CSU (strong recommendation/clinical consensus, accepted with 100%).

Reasoning/summary from discussion

In the previous version of the guidelines, the recommendation to limit routine diagnostic measures in CSU was based on the notion that the diagnostic workup in CSU patients should be a two-step approach: Step one is aimed at the exclusion of severe underlying diseases and avoidance of NSAIDs (routine/basic diagnostic measure to be performed in all patients) and Step two is the identification of underlying causes (extended diagnostic measures as indicated by patient history; to be performed in patients with longstanding and/or severe disease). In the previous guidelines, this conclusion was based on the fact that no new literature had been published contradicting this approach.

See Supporting Evidence in Table 9.

Table 9.  
Investigated studyStudy designP-value outcomeLimitationsQualityImportanceYear
  1. n.a., not applicable.

Smith [12]Systematic review of 29 studiesn.a.NoneHighHigh2011
Tarbox, Gutta [13]Retrospective analysis of a random sample of adult patients with urticaria and/or angioedema from 2001 to 2009, 356 cases in totaln.a.Diagnosis in patients was not standardized but based on individual decisions of differently treating physiciansLowHigh2011
Should extended diagnostic measures be performed in CSU?

We recommend for only limited extended diagnostic measures in CSU based on patient history (strong recommendation/clinical consensus, accepted with 100%).

Reasoning/summary from discussion

The previous version of the guideline recommends the use of extended diagnostic measures in CSU patients who exhibit a severe and/or longstanding disease and who provide clues for underlying cause(s) from their history. The current revision and update of the guideline maintains this recommendation. Disease activity and duration should be assessed. If the search for underlying causes is warranted, patients should be investigated for clues by taking a detailed history. For example, gastric pain may point to Helicobacter pylori infection, coexisting autoimmune disorders may suggest autoreactive mechanisms, reports of exacerbation of symptoms following the consumption of certain foods may indicate pseudoallergy as the cause. Several studies have shown the use of extended diagnostic measures to be helpful in the identification of underlying causes and in improving patient management if based on the patient's history.

See Supporting Evidence in Table 10.

Table 10.  
Investigated studyStudy designP-value outcomeLimitationsQualityImportanceYear
  1. n.a., not applicable.

Smith [12]Systematic reviewn.a.Divergent studies included. In summary, additional tests are valuable only when based on history of patientsHighHigh2011
Should routine diagnostic measures be performed in inducible, nonspontaneous subtypes of urticaria?

We recommend limiting routine diagnostic measures to determining the threshold of eliciting factors in inducible urticaria subtypes (strong recommendation/clinical consensus, accepted with 100%).

Reasoning/summary from discussion

According to the existing version of the guidelines, routine diagnostic measures in inducible, nonspontaneous subtypes of urticaria should be limited to determining the nature of the inducing trigger and its threshold. This recommendation is based on the fact that the triggers, but not the underlying factors, are not known to cause the majority of inducible urticaria subtypes, so attempts to identify them are generally futile. Routine and specific diagnostic measures are thus only warranted in cases where CSU coexists in the same patient or in rare subtypes of urticaria, for example cold urticaria where underlying causes have been identified in few cases. Since the last guideline was published, no new evidence has been published.

See Supporting Evidence in Table 11.

Table 11.  
Investigated studyStudy designP-value outcomeLimitationsQualityImportanceYear
  1. n.a., not applicable.

Zuberbier et al. [1]S3 level guidelinen.a.Based on few studies with low-level evidence having investigated the causative factors of inducible urticaria subtypesHighHigh2009
Which instrument should be used to measure QoL in urticaria?

We recommend using the validated Chronic Urticaria QoL.

Questionnaire (CU-Q2oL) and The Angioedema Quality of Life Questionnaires (AE-QoL) instruments for assessing QoL impairment and to monitor disease activity (strong recommendation/clinical consensus, accepted with 100%).

Reasoning/summary from discussion

Previous studies have shown that the generic QoL instruments in medicine and even dermatology are not disease specific enough to really measure the impact of urticaria (both wheals and angioedema). Disease-specific instruments have been developed, and they have been recommended in the last guideline since they were validated. Therefore, we recommend using the validated CU-Q2oL and AE-QoL instruments for assessing QoL impairment and to monitor disease activity.

See Supporting Evidence in Table 12.

Table 12.  
Investigated studyStudy designP-value outcomeLimitationsQualityImportanceYear
  1. RPC, randomized placebo controlled; n.a., not applicable.

Baiardini et al. [14]Consensus recommendationsn.a.No original data presentedHighHigh2011
Brzoza et al. [15]Polish validation study, prospective, SKINDEX and DLQI controlled, n = 126n.a.Was not used to assess treatment responsesHigh 2011
Kocaturk et al. [16]n.a. prospective    2012
Maurer et al. [17]n.a. prospective, multicenter, RPC Was not designed or powered to validate CU-Q2oL as a tool for measuring treatment responsesHigh 2011
Mlynek et al. [18]n.a. prospective    2009
Weller et al. [19]n.a. prospective    2012
Krause et al. [20]n.a. prospective    2012
Should patients with an allergic sensitization (positive specific IgE/skin prick test) avoid certain food items?

We recommend that patients with a known allergic sensitization based on specific IgE to food should only avoid these food items if there is relevant information, for example double-blind (DB) oral provocation test or a clear history, to prove that the sensitization has a clinical relevance for urticaria (strong recommendation/high level of evidence, accepted with 100%).

Reasoning/summary from discussion

In the previous guidelines, it was recommended that patients with a known allergic sensitization based on specific IgE to food should only avoid these items, if there is relevant information (e.g., DB oral provocation test or a clear history) to prove that the sensitization has a clinical relevance for urticaria. In addition, however, it needs to be noted that food-allergic reactions, for example gastrointestinal problems, can occur independently of the urticaria. The recommendation is in line with the general principle of allergy that allergens should be avoided in those cases where clinically relevant symptoms are proven. In line with other guidelines in allergy, sensitization alone is no reason to avoid an allergen (strong recommendation/high level of evidence).

See Supporting Evidence in Table 13.

Table 13.  
Investigated studyStudy designP-value outcomeLimitationsQualityImportanceYear
  1. n.a., not applicable.

Zuberbier et al. [2]S3 level guidelinen.a.NoneHighHigh2009
Brozek, Bousquet [8]WHO guidelinen.a.None, based on GRADEHighHigh2010
Boyce et al. [21]US guidelinen.a.None, based on GRADEHighHigh2011
Should treatment aim at complete symptom control in urticaria?

We recommend aiming for complete symptom control in urticaria as safely as possible [strong recommendation/clinical consensus following the WHO constitution in conformity with the Charter of the United Nations (UN)] (accepted with 97%).

Reasoning/summary from discussion

The previous guidelines recommended aiming for complete symptom control in urticaria. A number of studies have shown that using the algorithm proposed, it is in many patients possible to achieve complete symptom control. Our recommendation is based on the principles of medicine laid down in the WHO constitution in conformity with the Charter of the UN: Health is a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity. The enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition [22]. It is thus required to offer the patient as much benefit as possible. The recommendation can thus be maintained.

See Supporting Evidence in Table 14.

Table 14.  
Investigated studyStudy designP-value outcomeLimitationsQualityImportanceYear
  1. n.a., not applicable.

Zuberbier et al. [2]S3 level guidelinen.a.NoneHighHigh2009
Are modern second-generation H1-AHs to be preferred over first-generation H1-AHs in the treatment of urticaria?

We recommend that modern second-generation H1-AHs are to be preferred over first-generation H1-AHs in the treatment of urticaria (strong recommendation/high level of evidence, accepted with 95%).

Discussed alternatives:

  1. We recommend the use of modern second-generation H1-AHs over first-generation H1-AHs in the treatment of urticaria (strong recommendation/high level of evidence, voting result 97%).
Reasoning/summary from discussion

We recommend second-generation over first-generation oral H1-AHs (strong recommendation/high-quality evidence). In line with the ARIA guideline for patients with allergic rhinitis (Brozek et al. [20]), this recommendation places a relatively high value on the reduction of adverse effects and a relatively low value on comparative efficacy of second-generation vs first-generation oral H1-AHs. Already the previous guidelines have recommended to prefer modern second-generation AHs over first-generation H1-AHs in the treatment of urticaria. Since publishing the previous guideline, no new studies with head-to-head trials showing a possible improved efficacy of first-generation H1-AHs have been published but new reviews on the risks of first-generation H1-AHs are available. Based on the benefit/risk ratio, first-generation H1-AHs carry a high underestimated risk potential also when given in the evening (changes in REM pattern, hangover of impaired cognitive functions the next day) and thus should be avoided in the treatment of urticaria.

See Supporting Evidence in Table 15.

Table 15.  
Investigated studyStudy designP-value outcomeLimitationsQualityImportanceYear
  1. n.a., not applicable.

Zuberbier et al. [2]S3 level guidelinen.a.Based on few studies with low-level evidenceHighHigh2009
Church, Maurer [23]Systematic reviewn.a.NoneHighHigh2010
Are modern second-generation AHs as first-line treatment in urticaria to be preferred over other licensed medication?

We recommend that modern second-generation H1-AHs are to be used as first-line treatment of urticaria (strong recommendation/high level of evidence, accepted with 100%).

Reasoning/summary from discussion

Modern second-generation H1-AHs have been recommended as first-line treatment in urticaria in the previous guideline. In fact, AHs are the only licensed treatment in urticaria except for corticosteroids in acute urticaria. Using modern second-generation H1-AHs as treatment in all subtypes of urticaria has been shown to be efficacious in many trials for all licensed modern second-generation H1-AHs. Modern second-generation H1-AHs have furthermore proven to be of excellent safety and are available at low cost. The recommendation of the previous guideline to use modern second-generation H1-AHs that do not cause sedation can therefore be maintained (strong recommendation/high-quality evidence). This recommendation does not exclude the option that in acute urticaria, or acute exacerbations of CU, corticosteroids may and should be applied simultaneously if symptom severity does not allow a stepwise administration.

See Supporting Evidence in Table 16.

Table 16.  
DrugDaily doseDurationN active drug/placeboStudy designP < 0.05 vs PLP < 0.05 vs compared drugRemarksLimitationsQualityImportanceYearCitation
  1. Az, azelastine; Cet, cetirizine; Plc, placebo; Eb, ebastine; Bila, bilastine; Levo, levocetirizine; DB, double blind; PC, placebo controlled; COMP, comparison; CRO, cross-over; MC, multicenter; Astem, astemizole; Terf, terfenadine; Oxa, oxatomide; Des, desloratadine; Miz, mizolastine; Lor, loratadine.

Azelastine vs cetirizine4, 10 mg2 weeks73/Az, 23/Cet (Plc 28)DB PC COMPYesNoPruritus: Az > Cet; whealing: Cet > AzPatients with urticaria were studied together with patients with other allergic diseases, for example allergic rhinitis  1998Henz et al. [24]
Azelastine vs ebastine4, 10 mg3 weeksAz 17, Eb 17, Plc 18DB PC MC COMPYesNo 0HighHigh2001Camarasa et al. [25]
Bilastine vs levocetirizine20, 5 mg4 weeks173 ( Bila) 165 (Levo) Plc 184DB PC COMPYesNo 0HighHigh2010Zuberbier, Oanta [26]
Cetirizine vs cetirizine10 or 20 mg15 days30 CetDB CROYesPatients with angioedema were excluded0HighHigh1988Juhlin and Arendt [27]
Cetirizine vs astemizole

10 mg

10 mg

4 weeks62 Cet, 62 Astem, 63 PlcDB COMPYesWheal AS; Cet > Ast (.04)0HighHigh1990Alomar et al. [28]
Cetirizine10 mg 28DB PC CROYes 0HighHigh1991Goh et al. [29]
Cet, Astem10 mg4 weeks62 Cet, 62 Astem (63 Plc)DB PC CROYesn.s. 0HighHigh1991Juhlin [30]
Cetirizine vs terfenadine10 mg, 2 ×  60 mg20 days15 Cet, 15 TerfDB COMPYesCet > Terf0HighLow1993Andri et al. [31]
Cetirizine vs oxatomide5 mg Cet, 25 mg Oxa4 weeks28 Cet, 29 OxaDB MC COMP (children 2–6 years)NoChildren with angioedema were excluded0HighHigh2001La Rosa et al. [32]
Cetirizine vs fexofenadine10 mg Cet, 120 Fex4 weeks52 Cet, 45 FexDB COMPYes    2004Handa et al. [33]
Desloratadine5 mg6 weeksDes 95 (Plc 95)DB PC MCYes 0HighHigh2001Ring et al. [34]
Ebastine10 mg2 weeksEb 100 (Plc 104)DB PC MCYes 0HighHigh1991Peyri and Marron [35]
Ebastine vs terfenadine10 mg Eb, 120 mg Terf12 weeks69 Eb, 69 Plc, 69 TerfDB PC MC COMPYesNo 0HighHigh1996Kalis [36]
Fexofenadine20, 60, 120, or 240 mg4 weeksFex 20  mg: 90, 60 mg: 90, 120 mg: 77, 240  mg 82 – all 2 × daily, Plc: 79DB PC MCYesFex 60 = 120  = 240 > 20  mg – Fex improved performance/ work productivity – BID trend to 240 superior 120   2000Nelson et al. [37]
Fexofenadine2 × 60 mg4 weeks169 Fex, 158 PlcDB PC MCYes Sum of two identical studiesHighHigh2000Thompson et al. [38]
Fexofenadine2 × 10 mg (78) or 2 ×  60 mg (75) or 2 × 120  mg (73)1 week226–2 ×  10 mg (78), 2 ×  60 mg (75), 2 ×  120 mg (73)DB dose findingYes (compared to Fex 2 ×  10 mg)Fex 2 × 60 (n = 75) and 2 × 120 (n = 76) >2  × 10 mg (n = 75), efficiency proven in Japanese patients similar to American patients0HighHigh2001Kawashima and Harada [39]
Fexofenadine180 mg3 weeks21 Fex, 21 PlcDB PCYes Low numberHighHigh2002Degonda et al. [40]
Mizolastine10 mg4 weeks28 Miz, 28 PlcDB PC MCYes Low number, two centers onlyHighHigh1996Brostoff et al. [41]
Mizolastine, loratadine10 mg Miz, 10 mg Lora4 weeks88 Miz, 79 Lor, 80 PlcDB PC MC COMPYesNoNo difference with respect to angioedema0HighHigh1999Dubertret et al. [42]
Mizolastine10 mg4 weeks39 Miz, 39 PlcDB PC MCYes Not a primary report – cannot be included in this evaluationLowLow1999Ring et al. [43]
Mizolastine vs loratadine10 mg Miz, 10 mg Lor4 weeks26 Miz, 35 LorDB COMPNoMiz had a tendency to better reduce angioedema and the mean total duration of episodes0HighHigh2000Leynadier et al. [44]
Rupatadine10 or 20 mg4 weeks10 mg–112; 20 mg–109 (113)DB PC MCYes  0HighHigh2007Gimenez-Arnau et al. [45]
Rupatadine5, 10 or 20 mg4 weeks5 mg–68; 10 mg–73; 20 mg–67 (69)DB PCYes Trend analysis showed a dose- dependent improvement0HighHigh2007Dubertret et al. [46]
Levocetirizine5 mg4 weeks81 (85)DB PC MCYes  0HighHigh2006Kapp and Pichler [47]
Is an increase in the dose to fourfold of modern second-generation H1-AHs useful as second-line treatment and to be preferred over other treatments in urticaria?

We recommend a trial of up to fourfold dose of modern second-generation H1-AHs as second line in the algorithm of treatment (strong recommendation/high level of evidence, accepted with 98%).

Reasoning/summary from discussion

This treatment has meanwhile shown to be efficacious both in CSU and in inducible forms of urticaria. However, it must be noted that an increase in doses is not in the license of any of the modern second-generation H1-AHs (except 1- to 5-fold in fexofenadine and twofold in ebastine). It is, however, in the license of some old-generation sedating AHs, for example up to 10-fold for hydroxyzine. Other alternative medications investigated so far in urticaria are also not licensed and the licensed AHs all have a safety dossier on doses of at least up to fourfold, but dose-dependent side-effects vary between different modern second-generation AHs. Looking at the risk/benefit ratio with good high-quality level of evidence regarding the safety of updosing and sufficient evidence of the efficacy of updosing, the recommendation can be made to consider updosing up to fourfold as second level in the algorithm in the treatment of urticaria (strong recommendation/high-quality evidence for safety/high-quality evidence for efficacy in CU and cold urticaria; low-quality evidence for other subtypes of urticaria and no evidence in acute urticaria except widespread clinical use as direct trials are missing but a high-level circumstantial evidence based on the mode of action that updosing is useful also in other subtypes of urticaria). This recommendation also puts an emphasis on low costs compared to treatment with cyclosporin or OMA which are also part of the algorithm in level 3.

See Supporting Evidence in Table 17.

Table 17.  
DrugDaily doseDurationN active drug/placeboStudy designP < 0.05 P vs PLP < 0.05 P vs compared drugRemarksLimitationsQualityImportanceYearCitation
  1. AH, antihistamine; ASST, autologous serum skin test; CU, chronic urticaria; COMP, comparison; CSU, chronic spontaneous urticaria; DB, double blind; Des, desloratadine; Levo, levocetirizine; MC, multicenter; PC, placebo controlled; Rup, rupatadine; Plc, placebo; RPC, randomized placebo controlled; n.a., not applicable; n.s., nonsignificant.

Cetirizine10 vs 30 mg2–1 week 10 mg, 1 week 30 mg22Open-label CSUn.a.n.s.(i) Open label; (ii) only increased to threefold not fourfold as in guidelineSee remarks. ASST more frequently positive (72%) than in average CU population (approx. 30%)LowHigh2007Asero [48]
Rupatadine10 vs 20 mg4 weeks112 Rup 10 mg, 109 Rup 20 mg, 113 PlcDB, PC, MCYes0.01  HighHigh2007Gimenez-Arnau et al. [45]
Rupatadine10 vs 20 mg Pooled data from 2 DB, RPC, MCAnalysis of pooled data from 2 DB, PC, MC CSU20 vs Plc 00.01 Pooled data analysisHighHigh2009Gimenez-Arnau et al. [49]
Levocetirizine vs desloratadine5, 10, 20 mg4 weeks40 Levo, 40 Des

DB/COMP/CO

CSU unresponsive to AH single dose

Des 5 vs 20

P = 0.02, Lev 5 vs 20 P < 0.001

Des 5 vs 20

P = 0.02, Lev 5 vs 20 P < 0.001

Study shows that also switching antihistamine may be beneficial in some patientsNoneHighHigh2010Staevska et al. [50]
Desloratadine5–20 mg Plc8 weeks30

DB/CO/Plc

Cold urticaria

Yes

0.01

20 vs 5 mg

 NoneHighHigh2009Siebenhaar et al. [51]
Desloratadine5, 10, 20 mg6 weeks155 mg (n = 13) vs escalating 5–10–20 mg is cold urticaria (n = 28)n.a.0.05 Plc, 20 mg Des vs constant dose 5 mg    2012Magerl et al. [52]
Rupatadine20 g2 weeks21

DB/PC

Cross-over

Yes Complete response in 52%None  2010Metz et al. [53]
Various AHn.a.n.a.368Questionnaire to patients retrospectively  75% of patients reported to have updosed on physician's suggestion themselves with good successRetrospective   Weller et al. [54]
Various AHn.a.n.a.776Cross-sectional physician-based survey  25% of physicians use high-dose AH treatment in daily practice as second choice if AH single dose failsRetrospective   Weller et al. [55]
Bilastine20, 40, 80 mg12 weeks20DB, RPC, cross-over PYesn.a.Cold urticariaNoneHighHigh2012Krause et al. [56]
Are H2-AHs useful in the treatment of urticaria as third-line therapy?

We suggest the use of H2-AHs as add-on therapy to modern second-generation H1-AHs as a possible alternative treatment but not as first, second, or third line in the algorithm of treatment of urticaria (low recommendation/low level of evidence, voting result, accepted with 88%).

Discussed alternatives:

  1. We recommend a trial of H2-AHs as add-on therapy to modern second-generation H1-AHs as third line in the algorithm of treatment of urticaria (strong recommendation/low level of evidence) (voting result, <50%).
  2. We suggest a trial of H2-AHs as add-on therapy to modern second-generation H1-AHs but not as third line in the algorithm of treatment of urticaria (low recommendation/low level of evidence, voting result, <50%).
  3. We do not recommend a trial of H2-AHs as add-on therapy to modern second-generation H1-AHs in the algorithm of treatment of urticaria (strong recommendation/low level of evidence, voting result, <50%).
  4. We do not recommend a trial of H2-AHs as add-on therapy to modern second-generation H1-AHs (strong recommendation/low level of evidence, voting result, <50%).
  5. We do not recommend the use of H2-AHs as add-on therapy to modern second-generation H1-AHs (strong recommendation/low level of evidence, voting result, <50%).
Reasoning/summary from discussion

A recent Cochrane analysis found that evidence does not support the previous recommendation to use H2-AHs because evidence of efficacy is lacking in view of the fact that no new studies have been performed. H2-AHs are thus not recommended in the algorithm of treatment (strong recommendation/high-quality evidence) but could in individual cases be considered as alternative treatment in level 3 as the costs are very low and they are available worldwide (weak recommendation/low-quality evidence).

See Supporting Evidence in Table 18.

Table 18.  
Investigated studyStudy designP-value outcomeLimitationsInconsistency, indirectness, imprecisionQualityImportanceYear
  1. n.a., not applicable.

Fedorowicz [57]Cochrane reviewn.a.Based on limited number of studies of mostly ow quality HighHigh2012
Is cyclosporin A useful as add-on treatment in patients unresponsive to high doses of H1-AHs as third-line treatment?

We recommend a trial of cyclosporin A as add-on therapy to modern second-generation H1-AHs as third line in the algorithm of treatment of urticaria (strong recommendation/high level of evidence, voting result, accepted with 100%).

Reasoning/summary from discussion

In the previous guidelines, cyclosporin A as add-on treatment to fourfold doses of new-generation oral H1-AHs has been recommended as fourth line of treatment in the algorithm. This recommendation was already based on high-quality placebo-controlled double-blind randomized trials showing efficacy and safety. Since then, new trials have confirmed these data. We recommend using cyclosporin A as an add-on treatment in patients unresponsive to high doses of H1-AHs as third-line treatment in the appropriate clinical context, that is, no past history of malignancy, HIV, or other contraindications.

See Supporting Evidence in Table 19.

Table 19.  
DrugDaily doseDurationN active drug/placeboStudy designP < 0.05 vs PLP < 0.05 vs compared drugRemarksLimitationsQualityImportanceCitation
  1. CyA, cyclosporin; DB, double blind; Plc, placebo; PC, placebo controlled; n.a., not applicable.

Cyclosporin2.5 mg/kg4 weeks51 CyAControlledn.a.n.a. Not DB, not PCLowLowSerhat Inaloz et al. [58]
Cyclosporin + 20 mg Cet vs Plc + 20 mg Cet4 mg/kgInitial 4 weeks20 CyA, 10 PlcDB PCYesn.a. 0HighHighGrattan et al. [59]
Cyclosporin + Cet5 mg/kg + 10 mg Cet16 weeks DB PCYesn.a.Only evaluated as in guideline reports 1 and 30HighHighVena et al. [60]
Cyclosporin6 mg/kg>1 week3Uncontrolledn.a.n.a. Uncontrolled, not DB, not PCLowLowFradin et al. [61]
Cyclosporin3 mg/kg for 6 weeks, followed by 3 weeks of 2 mg/kg per day, and then 3 weeks of 1 mg/kg per day6 months19Controlledn.a.n.a. Not DB, not PCLowLowToubi et al. [62]
Cyclosporin3 mg/kg8 weeks7Retrospective uncontrolled  Only study in children, complete response in allRetrospective/small numberLowHighDoshi and Weinberger [63]
Cyclosporin1.8 ± 1.1 mg/kgn/a68Retrospective chart reviewn.a.n.a.>50% complete responseRetrospective, chart reviewLowLowHollander et al. [64]
Is OMA useful in the treatment of patients unresponsive to high doses of H1-AHs as third-line treatment?

We recommend a trial of OMA as add-on therapy to modern second-generation H1-AHs as third line in the algorithm of treatment of urticaria (strong recommendation/high level of evidence, accepted with 100%).

Reasoning/summary from discussion

In the previous guidelines, OMA was suggested as add-on treatment to fourfold doses of new-generation oral H1-AHs as a fourth level of treatment in the algorithm. This recommendation is now further supported by high-quality placebo-controlled double-blind randomized trials showing efficacy and safety. We thus recommend the use of OMA in those patients not responding to fourfold doses of new-generation oral H1-AHs based on RCTs showing an excellent risk/benefit ratio in this group of patients. There are numerous other case reports that support these observations [65-69].

See Supporting Evidence in Table 20.

Table 20.  
Urticaria typeDoseDurationN active drug/ placeboStudy designP < 0.05 vs PLP < 0.05 vs compared drugRemarksLimitationsQualityImportanceReference
  1. CSU, chronic spontaneous urticaria; OMA, omalizumab; RDBPC, randomized double blind placebo controlled; Plc, placebo; DBPC, double blind, placebo controlled; PC, placebo controlled; n.a., not applicable.

CSUAsthma dosing scheme, no minimum total IgE16 weeksOMA = 12, Plc = 12Open, cross-overYesn.a. Only autologous serum skin test positiveLowHighKaplan et al. [70]
CSUOMA 75–375 mg SC once every 2 or 4 weeks); asthma dosing scheme24 weeksOMA = 27, Plc = 22DB PCyesn.a. Only IgE-anti-TPO + patientsHighHighMaurer et al. [17]
CSU75 vs 300 vs 600 mg add-on to H1-antihistamine4 weeks (+12  weeks of follow-up)300 mg = 25, 600 mg = 21, 75 mg = 23, placebo = 21DBPCYes, for 300 and 600 mgn.a. Single doseHighHighSaini et al. [71]
CSU300 vs 150 vs 75 mg12 weeks (+16  weeks of follow-up)N = 322 (300 mg  = 79, 150 mg = 82, 75 mg = 82, placebo = 79)DBPCYes, for 150 and 300 mgn.a.  HighHighMaurer et al. [72]
Cold U375 mg every 2 weeks>5 months1Uncontrolled n.a. Case report  Boyce [73]
Solar U150 mg every 4 weeks>4 weeks1Uncontrolled n.a. Case reportLowHighGuzelbey et al. [74]
Chol U300 mg every 2 weeks>22 weeks1Uncontrolled n.a. Case reportLowHighMetz et al. [75]
Delayed pressure U150 mg every 2 weeks>3 months1Uncontrolled n.a. Case reportLowHighBindslev-Jensen and Skov [76]
Heat U450 mg every 2 weeks>19 months1Uncontrolled n.a. Case reportLowHighBullerkotte et al. [77]
Symptomatic dermographism300 mg/month>6 months2Uncontrolled n.a. Case reportLowHighKrause et al. [65]
OMA0.016 mg/kg/l U/ml per month4 weeks12Controlled, single blindyesn.a. Single blindLowHighKaplan et al. [70]
OMA75–375 mg, dose determined by using the approved asthma dosing table once every 2 or 4  weeks24 weeks27 OMA, 22 PlcMulticenter, RDBPC studyyesn.a.    Maurer et al. [17]
Should oral corticosteroids be used in the treatment of urticaria?

We recommend against the long-term use of systemic corticosteroids in urticaria (strong recommendation/high level of evidence, accepted with 99%).

and

We suggest a trial of a short course of systemic corticosteroids in urticaria as third-line therapy or as an option for acute exacerbation (weak recommendation/low level of evidence, accepted with 88%).

Discussed alternatives:

  1. We suggest a trial of a short course of systemic corticosteroids in urticaria as third-line therapy (weak recommendation/low level of evidence, voting result, <50%).
  2. We recommend a trial of a short course of systemic corticosteroids in urticaria as third-line therapy (strong recommendation/low level of evidence, voting result, <50%).
  3. We recommend a trial of a short course of systemic corticosteroids in urticaria as third-line therapy or as an option for acute exacerbation (strong recommendation/low level of evidence, voting result, <50%).

At present, topical corticosteroids are successfully used in many allergic diseases, but in urticaria topical steroids are not helpful (with the possible exception of pressure urticaria on the soles of the feet as alternative therapy with low evidence). If corticosteroids are used, systemic administration at doses between 20 and 50 mg/day is required with inevitable side-effects in the long term. Depending on the country, it must further be noted that steroids are also not licensed for CU (e.g., in Germany, prednisolone is licensed only for acute urticaria). Based on a risk/benefit ratio with other alternative medications being available, we thus recommend against the long-term use of corticosteroids outside specialist clinics (strong recommendation/high quality of evidence). For acute urticaria and acute exacerbations of CSU not responding to modern second-generation AHs, a short course of corticosteroids may, however, be required (in an emergency) and also possibly be beneficial to restore responsiveness to AHs and reduce disease duration warranting a suggestion to use this as an option in the third level.

See Supporting Evidence in Table 21

Table 21.  
DrugDaily doseDurationN active drug/placeboStudy designP < 0.05 vs PLP < 0.05 vs compared drugRemarksLimitationsQualityImportanceYearCitation
  1. AH, antihistamine; n.a., not applicable.

Prednisone25 mg/day on days 1, 2, and 3; 12.5 mg/day on days 4, 5, and 6; and 6.25 mg/day on days 7, 8, 9, and 1010 days90Openn.a.n.a.Included only patients refractory to standard doses of ns H1-AHs. In 40/86 patients (47%), prednisone induced remission of the disease and subsequent control with AH at licensed doses only. Thirty-five patients responded well but relapsed when prednisone doses were tapered or shortly after withdrawalretrospective uncontrolledLowHigh2010Asero and Tedeschi [78]
Should leukotriene antagonists be used in the third-line treatment of urticaria?

We suggest a trial of montelukast as add-on therapy to modern second-generation H1-AHs as third line in the treatment of urticaria (weak recommendation/low level of evidence, accepted with 99%).

Discussed alternatives:

  1. We recommend a trial of montelukast as add-on therapy to modern second-generation H1-AHs as third line in the algorithm of treatment of urticaria (strong recommendation/low level of evidence, voting result, 86%).

In the previous guideline, leukotriene receptor antagonists had been recommended as third-line therapy in the algorithm as add-on therapy to modern second-generation H1-AHs based on low-quality evidence. Since then, only one new study and one systematic review have been published favoring this intervention but limiting it to montelukast as add-on therapy to modern second-generation H1-AHs. Based on a risk/benefit ratio with other alternative medications available and comparatively low costs, we thus recommend using montelukast as third-line therapy in the algorithm as add-on to dose fourfold modern second-generation H1-AHs.

See Supporting Evidence in Table 22.

Table 22.  
DrugDaily doseDurationN active drug/placeboStudy designP < 0.05 vs PLP < 0.05 vs compared drugRemarksLimitationsQualityImportanceYearCitation
  1. PC, placebo controlled; CRO, cross-over; DB, double blind; Plc, placebo; Cet, cetirizine; Des, desloratadine; Mont, montelukast; ASST, autologous serum skin test; AH, antihistamine; n.a., not applicable; ZAF, zafirlukast; CSU, chronic spontaneous urticaria.

Montelukast vs Cet on demand vs Plc + Cet on demand10 mg (cetirizine 10 mg on demand, also in Plc group)6 weeks each15 each groupSB PC CROYesn.a.2-week wash-out period between cross-overSingle blind, low numberLowHigh2002Erbagci [79]
Mont + Des vs Plc + Des vs Plc10 mg + DLOR 5 mg6 weeks25 Des + Plc; 26 Des + Mont 25 Plc + PlcDB PCYesYes1-week PL run-in, 1-week PL-wash-out phase; example of combination therapy AH + antileukotrieneLow number of patientsHighHigh 2004Nettis et al. [80]
Des, montelukast single or combination vs placebo5 Des, 10 months6 weeks (8 weeks later follow-up)120, 40DB PC Parallel groupsDes vs Plc < 0.01, Mont vs Plc < 0.01, Des + Mont vs Plc < 0.01, on TSS (total symptom score)Des vs Mont < 0.01Des and Mont both had excellent safetyLow number of patientsHighHigh2004Di Lorenzo et al. [81]
ZAF2 × 20 mg6 weeks46 in cross-overDB PC CRONon.a.No subgroup with benefit could be identified0HighHigh Reimers et al. [82]
Cetirizine monotherapy vs cetirizine combination with ZAF10 mg Cet (2 × 20 mg ZAF plus cetirizine 10 mg, diphenhydramine)3 weeks48, 47DB PC MCYes combination Cet + ZAF superior to Cet monotherapyn.a.Only patients resistant to prior run-in phase with Cet 10 mg/day were randomized; only ASST + CSU refractory to H1-AH monotherapy showed a benefit from the addition of ZAF to Cet0HighHigh2004Bagenstose et al. [83]
Symptoms and QoL            
10 mg montelukast as add-on to single dose ns antihistamine10 mg3 weeks22, Plc = nDB PC cross-over add-onyes, montelukast as add-on to AHsn.a.In small number of patients, standard dose of antihistamine was not standardized but prescribed AH was continued in patients refractory to AH treatment0HighHigh Kosnik and Subic [84]
Systematic reviewn.an.an.an.aYes, montelukast as add-on to AHsn.aCovers literature only until 2009 HighHigh Di Lorenzo et al. [85]
Is dapsone useful in the treatment of urticaria as third-line therapy?

At the present time, it is not possible to give a recommendation for or against treatment with dapsone (accepted with 97%).

Discussed alternatives:

  1. We recommend a trial of dapsone as add-on therapy to modern second-generation H1-AHs as third line in the algorithm of treatment of urticaria (strong recommendation/low level of evidence, voting result, 85%).
Reasoning/summary from discussion

In the previous guidelines, dapsone as add-on treatment to fourfold doses of new-generation oral H1-AHs has been suggested as fourth-level treatment in the algorithm. This recommendation was based on previous open RCTs showing a good risk/benefit ratio in this group of patients but put emphasis on low costs and worldwide availability. Although these arguments have not changed for the intervention on level 3, the level of evidence for other interventions in level 3 has increased. Therefore in comparison, the level of evidence for dapsone was too low to keep it in level 3. Before reaching a decision for or against dapsone, further trials of high quality are needed.

See Supporting Evidence in Table 23.

Table 23.  
DrugDaily doseDurationN active drug/placeboStudy designP < 0.05 vs PLP < 0.05 vs compared drugRemarksLimitationsQualityImportanceYearCitation
  1. Dap, dapsone; Des, desloratadine; Plc, placebo; n.a., not applicable.

Dapsone plus desloratadine vs desloratadine50 mg dapsone + 5 mg desloratadine12 weeks38 Dap + 27 Des, Plc + DesOpen randomized controlledn.a.0.001 Open studyLowHigh2008Engin and Ozdemir [86]
Should the same treatment algorithm be used in children?

We suggest the same treatment algorithm to be used in children with CU (weak recommendation/clinical consensus, accepted with 100%).

Discussed alternatives:

  1. We recommend the same treatment algorithm to be used in children with CU (strong recommendation/clinical consensus, voting result, 91%).
Reasoning/summary from discussion

Already in previous guidelines, the same algorithm has been suggested to be used in children, with the remark that high-quality evidence was only available for the first line of treatment with modern second-generation AHs. Those are also licensed in children. The lack of evidence is based on the fact that urticaria is rare in children and that those children who suffer from urticaria have less severe symptoms than many adults. Due to the low number of affected children, high-quality randomized trials are thus not feasible and none have been published so far on the level 2–4 treatment strategies except for one study with cyclosporin. Anyhow all drugs have been used and are licensed in children in other indications showing their safety. Based on this knowledge, it appeared to be the best suggestion to be offered to use the same algorithm for children.

See Supporting Evidence in Table 24.

Table 24.  
Investigated studyStudy designP-value outcomeLimitationsInconsistency, indirectness, imprecisionQualityImportanceYearCitation
  1. CSU, chronic spontaneous urticaria; AH, antihistamine; n.a., not applicable.

Cyclosporin in children with CSU refractory to AHOpenn.a.7 patient case reportsn.a.LowHigh2009Doshi and Weinberger [63]
Should the same treatment algorithm be used in pregnant women and during lactation?

We suggest the same treatment algorithm be used in pregnant women and during lactation in urticaria (weak recommendation/clinical consensus, accepted with 97%).

Discussed alternatives:

  1. We recommend the same treatment algorithm be used in pregnant women and during lactation in urticaria (strong recommendation/clinical consensus, voting result, 85%).
Reasoning/summary from discussion

Already in previous guidelines, the same algorithm has been suggested for use in pregnant or lactating women, with the remark that high-quality evidence was only available for the first line of treatment with modern second-generation AHs. Among these, loratadine has the best published safety record. The relative lack of evidence is based on the fact that high-quality randomized trials are not ethical and none have been published so far on alternative treatment strategies. The available safety data on loratadine are based on retrospective observations in women with allergic rhinitis but the safety data may well be extrapolated. Extrapolation of safety data can also be made for treatment options in levels 2–4 where drugs have been used in other indications. Based on this knowledge, it appeared to be the best suggestion to use the same algorithm for pregnant and lactating women in levels 1, 2, and 3. The decision must be made on individual basis.

Are pseudoallergen-free diets useful in the extended diagnostic program of CSU?

We recommend the use of pseudoallergen-free diets (N.B. the term in pseudoallergen-free diet is most widely used as the term suggested by official EAACI nomenclature is too long: nonallergic hypersensitivity reaction causing agent-free diet) in the extended diagnostic program of CSU in patients with daily or almost daily symptoms only (strong recommendation/high-quality evidence, accepted with 100%).

and

We suggest to use pseudoallergen-free diet in the management program only for those patients responding to the diet (weak recommendation/high-quality evidence, accepted with 89%).

Discussed alternatives:

  1. We recommend the use of pseudoallergen-free diets in the extended diagnostic program of CSU (strong recommendation/high-quality evidence, voting result, 72%).
  2. We recommend the use of pseudoallergen-free diets in the extended diagnostic and management program of CSU in patients with daily or almost daily symptoms only (strong recommendation/high-quality evidence, voting result, <50%).
  3. We recommend the use of pseudoallergen-free diets in the extended diagnostic and management program of CSU in patients with daily or almost daily symptoms only (strong recommendation/high-quality evidence, voting result, <50%).
  4. We suggest the use of pseudoallergen-free diets in the extended diagnostic and management program of CSU in patients with daily or almost daily symptoms only (weak recommendation/high-quality evidence, voting result, <50%).

Already in the previous guidelines, pseudoallergen-free diets have been recommended as part of the extended diagnostic program in CSU. This recommendation was already based on high-quality evidence but limited to only patients with CSU with daily or nearly daily symptoms. High quality was mainly based on controlled open studies but dietary intervention does not easily allow a DB PC setting. Since then, further studies showing the benefit of pseudoallergen-free diets in a subset of the urticaria patients have been published also in other cultural groups (Turkey). We recommend the use of pseudoallergen-free diets in the extended diagnostic program of CSU (strong recommendation/high-quality evidence).

See Supporting Evidence in Tables 2526.

Table 25. Studies investigated in guidelines version 2009
Author(s)Disease studiedNumber of patientsPositive reactions to food additivesProvocationImprovement on diet
  1. ASS, acetylsalicylic acid.

Warin and Smith [87]Chronic urticaria11159.5% (incl. ASS)Single blind, placebo controlled75%
Genton et al. [88]Chronic urticaria1788.2% (incl. ASS)Single blind93.3%
Michaelsson and Juhlin [89]Chronic urticaria and angioedema5275% (incl. ASS)Single blind

81.3% free of symptoms

6.3% improvement

Thune and Granhold [90]Chronic urticaria10062% (incl. ASS)Single blind

80.6% improvement

19.4% spontaneous improvement

Wüthrich and Fabro [91]Urticaria62026.6% (incl. ASS)Single blindOver 60% improvement
Juhlin [92]Chronic urticaria and angioedema in 9%33031%Single blindNo data
Ortolani et al. [93]Chronic urticaria7059.6% (incl. ASS)Single blind, placebo controlledNo data
Rudzki et al. [94]Chronic urticaria15831.6% No data
Ros et al. [95]Chronic urticaria75 Follow-up study

24% free of symptoms

57% improvement

Verschave et al. [96]Chronic urticaria67No 55% of all patients
Gibson and Clancy [97]Chronic urticaria76Up to 54%Single blind, placebo controlled

71.1% free of symptoms

19.7% improvement

9.2% refused diet of all patients

Kirchhof et al. [98]Chronic intermittent urticaria10039%DB, placebo controlled44%
Supramaniam and Warner [99]Urticaria and angioedema in 74.4%4324%DB, placebo controlled87.5%
Zuberbier et al. [100]Chronic urticaria and/or angioedema6719%DB, placebo controlled73% of all patients
Pigatto and Valsecchi [101]Chronic urticaria202 of 34837.3%DB, placebo controlled

62.4% improvement

17.3% no improvement

20.3% discontinued diet of all patients

Table 26. Studies published since 2009
Study designP-value outcomeLimitationsQualityImportanceYearCitation
  1. n.a., not applicable.

Prospective, open

n.a.

41% responder rate, n = 34

Controlled, openHighHigh2012Akoglu et al. [102]
Prospective, open

n.a.

34% responder rate, n = 140

Controlled, openHighHigh2010Magerl et al. [103]
Should modern second-generation AHs be taken regularly or as needed?

We recommend modern second-generation oral H1-AHs be taken continuously in the lowest necessary dose rather than on demand (strong recommendation/high-quality evidence, voting result, accepted with 98%).

Discussed alternatives:

  1. We recommend modern second-generation oral H1-AHs be taken regularly and not as needed (strong recommendation/high-quality evidence, voting results, <90%).
  2. We recommend modern second-generation oral H1-AHs be taken continuously and not as needed (strong recommendation/high-quality evidence, voting results, <90%).
  3. We recommend modern second-generation oral H1-AHs be taken continuously in the lowest necessary dose and not as needed (strong recommendation/high-quality evidence, voting results, <90%).
Reasoning/summary from discussion

The recommendation to take new-generation oral H1-AHs that do not cause sedation regularly and not as needed is based on low-quality evidence of one trial comparing both treatment options [104] but on high circumstantial evidence, because it (i) could be shown that modern second-generation AHs can suppress occurrence of new wheals and angioedema but not reduce time to spontaneous recovery of already existing wheals [105], (ii) high-quality evidence of good safety data and better QoL of patients while putting less emphasis on costs.

See Supporting Evidence in Table 27.

Table 27.  
Investigated studyStudy designP-value outcomeLimitationsQualityImportanceYearCitation
  1. Des, desloratadine; AH, antihistamine; n.a., not applicable.

Observation of resolution of wheals under different treatment optionsProspective, DB 5 vs 20 mg Des, n = 29n.a.Indirect high-quality evidence study showed that AH treatment could not enhance the resolution of already existing wheals at the time of administration on demandHighHigh2012Weller et al. [105]
Comparison of AH regularly on demandRandomized, double-blind, parallel group study, n = 46>0.05 HighHigh2008Grob et al. [104]
Should different H1-AHs be used at the same time?

We recommend preferably to updose modern second-generation oral H1-AHs that do not cause sedation up to fourfold (strong recommendation/high-quality evidence) instead of combining different H1-AHs at the same time (strong recommendation/low-quality evidence, accepted with 100%).

Reasoning/summary from discussion

We recommend preferably updosing with new-generation oral H1-AHs that do not cause sedation up to fourfold (strong recommendation/high-quality evidence) instead of mixing different H1-AHs at the same time, which has been proposed as this procedure is not off-label if licensed doses are used in contrast to updosing. This recommendation is based on the fact that updosing has been proven to be efficacious in RCTs which are missing for the alternative concept of mixing different H1-AHs. In a retrospective comparison, it was shown that updosing is superior to combining (low-quality evidence) as well as circumstantial evidence that different H1-AHs also exert other anti-inflammatory properties that are different from those preventing histamine receptor stimulation. These properties can be improved with updosing (low-quality evidence). In summary, updosing is better than mixing (strong recommendation/low-quality evidence).

See Supporting Evidence in Table 28.

Table 28.  
Investigated studyStudy designP-value outcomeLimitationsInconsistency, indirectness, imprecisionQualityImportanceYearCitation
  1. Plc, placebo.

 2 × 2 vs 3 × 2 vs 4 × 1 retrospectivePlc 0.01, 2 × 2 vs other treatmentsRetrospective, small numberNoneHighHigh2009Schulz et al. [106]
If there is no improvement, should higher than fourfold doses of H1-AHs be used?

We recommend preferably updosing with modern second-generation H1-AHs that do not cause sedation up to fourfold and to not further increase the dose (strong recommendation/low-quality evidence, accepted with 99%).

Reasoning/summary from discussion

This recommendation is based on the fact that updosing has previously been recommended in the guideline and has been proven to be efficacious and safe in RCTs for up to fourfold doses (see question 12) but studies are completely missing for the use of higher doses in urticaria.

See Supporting Evidence in Table 29.

Table 29.  
Investigated studyStudy designP-value outcomeLimitationsInconsistency, indirectness, imprecisionQualityImportanceYearCitation
  1. n.a., not applicable.

 S3 level guidelinen.a.None HighHigh2009Zuberbier et al. [2]

External review

  1. Top of page
  2. Abstract
  3. Methods
  4. External review
  5. Funding
  6. Future updates of the guidelines
  7. Conflicts of interest
  8. References

All societies involved in the consensus meeting were invited to comment on the final document within a timeframe of 4 weeks. No response was considered as approval. The IADVL had a number of specific comments regarding the specialties in the medical system of India. These were published in the guideline. The AAAAI participated in the process of developing these guidelines with input, review, and thoughtful comments, anyhow is not an endorsing founder society.

Funding

  1. Top of page
  2. Abstract
  3. Methods
  4. External review
  5. Funding
  6. Future updates of the guidelines
  7. Conflicts of interest
  8. References

The guidelines were funded solely by the participating societies who covered the costs of their delegates for the meeting as well as through the meetings organizers, GA2LEN, and EAACI. Participants except the panel members paid the fees covering costs for meals. The expenses for the literature search and methodological review were covered by European Centre for Allergy Research Foundation (ECARF), which is not supported by any pharmaceutical company. The funding body took no influence on the structure, process, or content of the guidelines.

Future updates of the guidelines

  1. Top of page
  2. Abstract
  3. Methods
  4. External review
  5. Funding
  6. Future updates of the guidelines
  7. Conflicts of interest
  8. References

The validity of these guidelines is 4 years (2016). Because new interventions may be licensed or relevant changes in information (e.g., on adverse events) may become available before this point, the steering committee will evaluate the need for an earlier update of the whole guidelines or individual questions at regular intervals.

Conflicts of interest

  1. Top of page
  2. Abstract
  3. Methods
  4. External review
  5. Funding
  6. Future updates of the guidelines
  7. Conflicts of interest
  8. References

Conflict of interests were declared by all participants prior to the consensus conference. They were assessed by the steering committee with respect to their acceptability. The assessment of the individual declaration of possible conflicting interests did not lead to the exclusion of any of the panel members. All panel members declared that they feel that their possible conflict of interests will not interfere in a relevant way with their voting behavior.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. External review
  5. Funding
  6. Future updates of the guidelines
  7. Conflicts of interest
  8. References