Position paper EAACI/GA2LEN/EDF/WAO guideline: management of urticaria This guideline is the result of a panel discussion during the Third International Meeting on Urticaria, Urticaria 2008, a joint initiative of the EAACI Dermatology Section, GA2LEN, EDF, and WAO. Urticaria is a heterogeneous group of diseases that result from a large variety of underlying causes, are elicited by a great diversity of factors, and present clinically in a highly variable way. The aim of treatment, This guideline, together with its sister guideline on the classification of urticaria (Zuberbier T, Asero R, Bindslev-Jensen C, Canonica GW, Church MK, Gimenez-Arnau AM et al. EAACI/GA2LEN/EDF/WAO Guideline: definition, classification and diagnosis of urticaria. Allergy 2009 64: 1417���1426), is the result of a consensus reached during a panel discussion at the Third Interna- tional Consensus Meeting on Urticaria, Urticaria 2008, a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-funded network of excellence, the Global Al- lergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO). As members of the panel, the authors had prepared their suggestions regarding management of urticaria before the meeting. The draft of the guideline took into account all available evidence in the literature (including Medline and Embase searches and hand searches of abstracts at international allergy congresses in 2004���2008) and was based on the existing consensus reports of the first and the second symposia in 2000 and 2004. These suggestions were then discussed in detail among the panel members and with the over 200 international specialists of the meeting to achieve a consensus using a simple voting system where appropriate. Urticaria has a profound impact on the quality of life and effective treatment is, therefore, required. The recommended first line treatment is new generation, nonsedating H1-antihistamines. If standard dosing is not effective, increasing the dosage up to four-fold is recommended. For patients who do not respond to a four-fold increase in dosage of nonsedating H1-antihistamines, it is recommended that second-line therapies should be added to the antihistamine treatment. In the choice of second-line treatment, both their costs and risk/benefit profiles are most important to consider. Corticosteroids are not recommended for long-term treatment due to their unavoidable severe adverse effects. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). T. Zuberbier1, R. Asero2, C. Bindslev- Jensen3, G. Walter Canonica4, M. K. Church1, A. M. Gim��nez-Arnau5, C. E. H. Grattan6, A. Kapp7, M. Maurer1, H. F. Merk8, B. Rogala9, S. Saini10, M. S��nchez-Borges11, P. Schmid-Grendelmeier12, H. Sch��nemann13, P. Staubach14, G. A. Vena15, B. Wedi7 1 Department of Dermatology and Allergy, Charit�� ��� Universit��tsmedizin Berlin, Berlin, Germany 2 Ambulatorio di Allergologia, Clinica San Carlo, Paderno Dugnano (MI), Italy 3 Allergy Centre, Department of Dermatology, Odense University Hospital, Odense Area, Denmark 4 Allergy and Respiratory Diseases, DIMI ��� University of Genoa, Genoa, Italy 5 Department of Dermatology, Hospital del Mar, IMAS, Universitat Aut��noma of Barcelona, Barcelona, Spain 6 Dermatology Centre, Norfolk & Norwich University Hospital, Norwich, UK 7 Department of Dermatology and Allergology, Hannover Medical University, Hannover, Germany 8 Department of Dermatology, University Hospital RWTH Aachen, Aachen, Germany 9Clinical Department of Internal Diseases, Allergology and Clinical Immunology, Medical University of Silesia, Katowice, Poland 10Department of Medicine, Johns Hopkins University, Baltimore, MD, USA 11 Allergy and Immunology Department, Centro Medico- Docente La Trinidad, Caracas, Venezuela 12 Allergy Unit, Department of Dermatology, University Hospital, Zurich, Switzerland 13 Department of Clinical Epidemiology & Biostatistics, Hamilton, Canada 14 Department of Dermatology, Johannes Gutenberg-University Mainz, Mainz, Germany 15 Unit of Dermatology, University of Bari, Bari, Italy Key words: consensus guideline treatment urticaria wheal. T. Zuberbier Charit�� ��� Universit��tsmedizin Berlin Allergie-Centrum-Charit�� Charit��platz 1 D-10117 Berlin Germany Accepted for publication 3 July 2009 Allergy 2009: 64: 1427���1443 �� 2009 John Wiley & Sons A/S DOI: 10.1111/j.1398-9995.2009.02178.x 1427

however, is the same for all types of urticaria: to achieve complete symptom relief. The management of urticaria is best subdivided into two basic lines of approach both of which should be considered in each patient: first, the identification and elimination of the underlying cause(s) and/or eliciting trigger(s), and, second, treatment aimed at providing symptom relief. Treating the cause is the most desirable option, but it is, unfortunately, not applicable in the majority of patients, especially in cases of inducible urticarias which are mainly idiopathic. Second best is avoidance of the eliciting trigger or stimulus, which can be instituted for the rare patients with IgE-mediated urticaria and partly, for those patients with physical urticaria. In the latter group, the impact of physical stimuli can be diminished and symptoms ameliorated by appropriate measures (e.g., cushioning in pressure urticaria). In spontaneous acute and chronic urticaria, treatment of associated infectious and/or inflammatory processes, including Helicobacter pylori-associated gastritis, parasitic diseases, or food and drug intolerance may be helpful in selected cases. In addition, it must be noted that some factors, e.g., analgesic drugs, can elicit new wheal formation as well as augment preexisting urticaria. Chronic urticaria is also recognized as stress ��� vulnerable disease in which psychological stress can trigger or increase itching. It is suggested that effective management process could take into account, at least in some of the patients, psycholog- ical factors (2���4). In all cases symptomatic relief should be offered while searching for causes. Symptomatic treatment is currently the most frequently used form of management. It aims ameliorating or suppressing symptoms by inhibiting the release and/or the effect of mast cell mediators and possibly other inflammatory mediators. The treatment options available have been evaluated in this guideline according to the following methods. Methods As members of the panel, the authors had prepared their sugges- tions regarding management of urticaria before the meeting. The draft of the guideline took into account all available evidence in the literature (including Medline and Embase searches and hand sear- ches of abstracts at international allergy congresses in 2004���2008) and was based on the existing consensus reports of the first and second symposia in 2000 and 2004 (5, 6). These suggestions were then discussed in detail among the panel members and with the participants of the meeting, to achieve a consensus using a simple voting system where appropriate. The participation of more than 200 specialists in urticaria from 33 countries ensured that this consensus included European and global regional differences in viewpoint and provided a basis for improved comparison of future studies in the field of urticaria. In the previous consensus document, studies were evaluated using the Methodology Checklist 2 for Randomized Controlled Trials (RCTs) of the Scottish Intercollegiate Guidelines Network (SIGN) resulting in the following 3-level code: ++, +, ). This code, together with the study type, decided the Level of Evidence (1++ to 1), 2++ to 2), 3, 4) that led to the Grade of Recommendation (A���D). However, the SIGN methodology does not assign a quality or level of evidence for the body of evidence and it is intended only for assessment of individual studies that are identified during the search process. However, in order to express the confidence in the totality of evidence an approach to assessing a body of evidence for a given questions is required. For the current guideline we used a pragmatic Grading of Recommendations Assessment, Develop- ment, and Evaluation (GRADE) approach transforming the al- ready existing evaluations of the literature according to the SIGN criteria for individual studies from the previous guideline and adding newly published studies (Table 1). We based our ratings on the levels of evidence we obtained using the SIGN methodology from the previous guidelines without re-examining the assessments. The key principle of the GRADE approach is to provide trans- parency and clear and explicit criteria for assessing the quality of evidence and grading the strength of recommendations (7���11). While recommendations in guidelines, in particular those developed Table 1. Evidence of identified literature sources The level of evidence provided by the study is derived from the code allocated for the methodological quality and the type of study, according to the Methodology Checklist 2: Randomized Controlled Trials of the Scottish Intercollegiate Guidelines Network (SIGN). 1++ High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias 1+ Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1) Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias 2++ High-quality systematic reviews of case���controlled or cohort or studies High quality case���controlled or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal 2+ Well conducted case���controlled or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal 2) Case���controlled or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal 3 Nonanalytic studies, e.g., case reports, case series 4 Expert opinion SIGN level of evidenceGRADE Quality of evidence 1++ High 1+ Moderate 1) Low 2++ Low 2+ Low 2) Very low 3 Very low 4 Very low Abbreviations used in this and subsequent tables: AH, antihistamine ns, nonse- dating RCT, randomized controlled trial s, sedating, sg, second generation. The following translation to the GRADE quality of evidence was used acknowledging that a more detailed assessment will possibly change the quality of evidence and that additional quality criteria are considered in GRADE. Zuberbier et al. 1428 �� 2009 John Wiley & Sons A/S Allergy 2009: 64: 1427���1443

with the GRADE approach, should ideally be based on well done systematic reviews, a more pragmatic approach to applying GRADE includes the identification of well done systematic reviews for a given clinical question or, alternatively, conducting a system- atic review. An even more pragmatic approach includes the use of informal summaries based on searches of the literature. This should be followed by grading the quality of evidence and strength of each recommendation. The key principle is to be transparent about the methods, in particular those that are used for summarizing the evidence and the key factors influencing a recommendation. For this Urticaria guideline 2008 update most of the sections did not follow systematic review methodology, but we did follow the general principles of GRADE for assessing the quality of evidence and strength of recommendations. Factors that influence the strength of a GRADE recommendation are the quality of the underlying evidence, the balance between desirable and undesirable effects and resources used for an intervention. Separation of the strength of a recommendation from the quality of supporting evidence is critical when making recommendations. The GRADE system permits strong recommendations supported by low or very rarely very low quality evidence from downgraded RCTs or observational studies. At the same time allowing weak recom- mendations based on high-quality evidence. While the former is a rare occurrence in the unusual case where other factors than the evidence from included studies that determine the strength of a rec- ommendation suggest this as the best course of action, weak rec- ommendations in the face of high quality evidence are less unusual. The guideline panel chose the words ��we recommend�� ��� for strong recommendations and ��we suggest�� ��� for weak recommendations in order to adhere to the same methodology as for development of the Allergic Rhinitis and its Impact on Asthma Guideline 2008 update (Table 2) (10). This same terminology has also been adhered to in those parts of the guideline where the assessment of the evidence was not done in full. Literature searching for all questions was done using PubMed/ MEDLINE and EMBASE together with hand-searching of abstracts of international allergy conferences in 2004���2008. We did not complete full systematic reviews for this guideline. Studies that had no English abstract were not systematically evaluated. Also excluded were those investigating terfenadine and astemizole, which have strong cardiotoxic effects. Participants of the conference that led to formulation of recom- mendations were presented with a draft version of this document and were asked to vote whether they agreed with specific parts of the text that referred to therapeutic options. Voting was preceded by discussion if disagreement was present. Strength of recommendation Recommendations are classified as ��strong�� or ��weak�� recommenda- tions, as recommended in the GRADE methodology. ��Strong�� rec- ommendations can be interpreted as: ��� Most individuals should receive the intervention ��� Most well informed individuals would want the recommended course of action and only a small proportion would not ��� Could be used for policy making or as or quality indicator. Table 2. Box of recommendations and suggestions for the management of urticaria We recommend the use of the treatment algorithm as described in Fig. 1 for the symptomatic treatment of chronic spontaneous urticaria (strong, low quality evidence). In patients with urticaria and no special indication, we recommend against the routine use of old sedating first generation antihistamines (strong recommendation, high quality evidence). We recommend against the use of astemizole and terfenadine (strong recommendation, high-quality evidence). We suggest the same first line treatment and up-dosing as described in Fig. 1 for children (weight adjusted) (weak recommendation, low-quality evidence). We suggest the same first line treatment as described in Fig. 1 in pregnant or lactating women with chronic spontaneous urticaria but safety data in a large meta-analysis is limited to loratadine (weak recommendation, very low-quality evidence). Remarks: higher doses may be required, but their safety profile needs to be carefully weighted against the potential additional benefit. If symptoms persist after 2 weeks If symptoms persist after 1-4 weeks If symptoms persist after 1-4 weeks Non sedating H1-antihistamine (nsAH) nsAH updosing (up to 4x) Add Leukotriene antagonist or change nsAH Exacerbation: Systemic Steroid (for 3 ���7 days) Add Ciclosporin A, H2-antihistamine, Dapsone, Omalizumab Exacerbation: Systemic Steroid (for 3 ���7 days) Figure 1. Recommended treatment algorithm for chronic urti- caria. Guideline: management of urticaria �� 2009 John Wiley & Sons A/S Allergy 2009: 64: 1427���1443 1429