This guideline, together with its sister guideline on the management of urticaria Zuberbier T, Asero R, Bindslev-Jensen C, Canonica GW, Church MK, Giménez-Arnau AM et al. EAACI/GA²LEN/EDF/WAO ...Guideline: Management of urticaria. Allergy, 2009; 64:1427-1443 is the result of a consensus reached during a panel discussion at the 3rd International 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 Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO). Urticaria is a frequent disease. The life-time prevalence for any subtype of urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria do not only cause a decrease in quality of life, but also affect performance at work and school and, as such, are members of the group of severe allergic diseases. 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 approaches for different subtypes of urticaria. The correct management of urticaria, which is of paramount importance for patients, is very complex and is consequently covered in a separate guideline developed during the same consensus meeting. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS).
Summary
Chronic spontaneous urticaria (CSU) is a mast cell‐driven disease that is defined as the recurrence of weals, angioedema or both for > 6 weeks due to known or unknown causes. As of yet, ...disease diagnosis is purely clinical. Objective tools are needed to monitor the activity of CSU and the efficacy of treatment. Recently, several reports have suggested that blood parameters may be considered as potential disease‐related biomarkers. Here, we reviewed available literature on blood biomarkers for CSU diagnosis, activity monitoring, duration, patient subgroup allocation or response to treatment. We performed a PubMed, Google Scholar and Web of Science search and identified and analysed 151 reports published prior to January 2016. We found strong evidence for significant differences between patients with CSU and healthy controls in blood levels or values of D‐dimer, C‐reactive protein (CRP), matrix metalloproteinase‐9 (MMP‐9), mean platelet volume (MPV), factor VIIa, prothrombin fragment 1 + 2 (F1 + 2), tumour necrosis factor, dehydroepiandrosterone sulphate and vitamin D. Also, there is strong evidence for a significant association between CSU activity and blood levels or values of D‐dimer, F1 + 2, CRP, IL‐6 and MPV. Strong evidence for reduced basophil count and high levels of IgG anti‐FcεRI in the subgroup of CSU patients with positive autologous serum skin test was shown. In contrast, the evidence for all reported blood biomarkers for differentiating CSU from other diseases, or a role in prognosis, is weak, inconsistent or non‐existent. Taken together, we identified 10 biomarkers that are supported by strong evidence for distinguishing patients with CSU from healthy controls, or for measuring CSU activity. There is a need for further research to identify biomarkers that predict outcome or treatment response in CSU.
Background
Cold contact urticaria (CCU) is characterized by itchy wheal and flare responses due to the release of histamine and other pro‐inflammatory mediators after exposure to cold. The treatment ...of choice is nonsedating antihistamines, dosages of which may be increased up to fourfold if standard doses are ineffective. Here, we assess the effects of a standard 20 mg dose and up‐dosing to 40 and 80 mg of bilastine in reducing the symptoms of CCU and inflammatory mediator release following cold challenge.
Methods
Twenty patients with CCU were included in this randomized, crossover, double‐blind, placebo‐controlled 12‐week study. They received placebo, 20, 40 or 80 mg of bilastine daily each for 7 days with 14‐day washout periods. The primary readout was change in critical temperature thresholds (CTT). Secondary readouts were changes in pruritus, levels of histamine IL‐6, IL‐8 and TNF‐α collected by skin microdialysis and safety and tolerability of bilastine.
Results
Bilastine 20 mg was highly effective (P < 0.0001) in reducing CTT. Up‐dosing to 80 mg significantly (P < 0.04) increased its effectiveness. At this dose, 19 of 20 (95%) patients responded to treatment, with 12 of 20 (60%) becoming symptom free. Only one patient was refractory to treatment. Microdialysis levels of histamine, IL‐6 and IL‐8 assessed 1–3 h after cold challenge were significantly (P < 0.05) decreased following up‐dosing with 80 mg bilastine. Bilastine treat‐ment was well tolerated without evidence of increased sedation with dose escala‐tion.
Conclusions
Bilastine was effective in reducing the symptoms of patients with CCU. Increased efficacy of bilastine with fourfold up‐dosing was without sedation and supports urticaria treatment guidelines.
This guideline 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 (GA(2) LEN), the European Dermatology Forum (EDF), and the World Allergy Organization (WAO) with the participation of delegates of 21 national and international societies. Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The life-time prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria do not only cause a decrease in quality of life, but also affect performance at work and school and, as such, are members of the group of severe allergic diseases. 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).
In the European Union (EU), between 44 and 76 million individuals of the 217 million EU employees suffer from allergic disease of the airways or the skin. Up to 90% of these persons are untreated or ...insufficiently treated. This has major socio-economic consequences such as absence from work (absenteeism), particularly reduced productivity at work (presenteeism).
We used published literature and online statistical information from Eurostat and Eurofound to assess the costs of allergic disease to society.
Allergies have an impact on direct, indirect, intangible and opportunity costs. Most importantly, for the EU, avoidable indirect costs per patient insufficiently treated for allergy range between €55 and €151 billion per annum due to absenteeism and presenteeism, that is, €2405 per untreated patient per year. On the other hand, appropriate therapy for allergic diseases is available at comparatively low costs at an average of €125 per patient annually, equalling only 5% of the costs of untreated disease, allowing potential savings of up to €142 billion.
A better care for allergies based on guideline-based treatment would allow Europe's economy substantial savings. In addition, allergies have an impact on learning and performance at school and university, leading to opportunity costs for society. This cannot be calculated moneywise but will have an impact in a modern knowledge-based society. Still allergies are trivialized in society, noting that the costs of therapy are paid by patients and healthcare services, whereas economic savings are made by employers and society. A change of this mindset is urgently needed.
Background
Chronic spontaneous urticaria (CSU) is considered an autoimmune disorder in 50% of cases at least, in which T‐ and mast cell mediators are considered to be the primary cause of symptoms. ...However, H1‐antihistamines, cyclosporine A, and omalizumab fail to achieve complete symptom amelioration in up to 70% of patients. This suggests that other inflammatory pathways are involved and that additional and more effective treatments need to be developed.
Objective
This preliminary report examines the possibility that interleukin‐17 (IL‐17), a cytokine involved in the pathogenesis of many autoimmune diseases, may contribute to CSU and its inhibition may offer a relevant therapeutic target.
Methods
The expression of IL‐17A in skin biopsies of 20 CSU patients and 10 healthy controls was determined by quantitative histomorphometry. We also assessed the response to secukinumab (anti‐IL‐17A) treatment patients of eight severe CSU (7‐day urticaria activity score UAS7 32‐40) who were H1‐antihistamine and omalizumab‐resistant.
Results
Increased numbers of CD4+ T cells and mast cells were present in both lesional and non‐lesional skin of CSU patients compared with healthy controls. Both types of cells were strongly positive for IL‐17A and found to be in close proximity to each other. All eight patients treated with the anti‐IL‐17A antibody, secukinumab, showed significant improvement in CSU disease activity. The action of secukinumab was shown to be relatively slow in onset. The significant reduction in disease activity from baseline UAS7 was demonstrated to be 55% and 82% at 30 and 90 days, respectively.
Conclusions
These findings suggest that IL‐17 is involved in the pathogenesis of CSU and that IL‐17 should be investigated as a therapeutic target in future studies with larger numbers of patients.
Summary
Background
Many physicians believe that the most effective way to treat chronic urticaria is to take a nonsedating second‐generation H1‐antihistamine in the morning and a sedating ...first‐generation H1‐antihistamine, usually hydroxyzine, at night to enhance sleep. But is this belief well founded?
Objectives
To test this belief by comparing the effectiveness and prevalence of unwanted sedative effects when treating patients with chronic spontaneous urticaria (CSU) with levocetirizine 15 mg daily plus hydroxyzine 50 mg at night (levocetirizine plus hydroxyzine) vs. levocetirizine 20 mg daily (levocetirizine monotherapy).
Methods
In this randomized, double‐blind, cross‐over study, 24 patients with difficult‐to‐treat CSU took levocetirizine plus hydroxyzine or levocetirizine monotherapy for periods of 5 days each. At the end of each treatment period, assessments were made of quality of life (Chronic Urticaria Quality of Life Questionnaire, CU‐Q2oL), severity of urticaria symptoms (Urticaria Activity Score, UAS), sleep disturbance during the night and daytime somnolence.
Results
Both treatments significantly decreased UAS, night‐time sleep disturbances and CU‐Q2oL scores (P < 0·001) without significant differences between the two. Compared with baseline, daytime somnolence was significantly reduced by levocetirizine monotherapy (P = 0·006) but not by levocetirizine plus hydroxyzine (P = 0·218). Direct comparison of the two treatment modalities in terms of daytime somnolence favoured levocetirizine monotherapy (P = 0·026).
Conclusions
The widespread belief that sleep is aided by the addition of a sedating first‐generation H1‐antihistamine, usually hydroxyzine, at night is not supported. These results are in line with the urticaria guidelines, which state that first‐line treatment for urticaria should be new‐generation, nonsedating H1‐antihistamines only.
What's already known about this topic?
The EAACI/GA2LEN/EDF/WAO guideline for management of urticaria recommends second‐generation ‘nonsedating’ H1‐antihistamines as first‐line treatment for chronic spontaneous urticaria (CSU).
However, it is common practice to add a sedating H1‐antihistamine, such as hydroxyzine, at night in the belief that it will reduce itch and improve the quality of sleep.
What does this study add?
This study compared 5‐day treatment of CSU with the second‐generation H1‐antihistamine, levocetirizine (20 mg daily), with levocetirizine (15 mg daily) plus hydroxyzine (50 mg nightly).
The treatments were equally effective in decreasing symptoms and night‐time sleep disturbances and increasing quality of life, but the addition of night‐time hydroxyzine significantly increased daytime somnolence.
The belief that addition of a night‐time sedating H1‐antihistamine is of benefit in the treatment of CSU is unfounded.
GA²LEN, the Global Allergy and Asthma European Network, has recently launched a program for the development, interaction, and accreditation of centers of reference and excellence in special areas of ...allergy embedded in its overall quality management of allergy centers of excellence. The first area chosen is urticaria. Urticaria is a common and debilitating condition and can be a challenge for both patients and treating physicians, especially when chronic. Centers of reference and excellence in urticaria (UCAREs) can help to improve the management of hard-to-treat conditions such as urticaria.
Here, we describe the aims, the requirements and deliverables, the application process, and the audit and accreditation protocol for GA²LEN UCAREs.
The main aims of GA²LEN UCAREs are to provide excellence in urticaria management, to increase the knowledge of urticaria by research and education, and to promote the awareness of urticaria by advocacy activities. To become a certified GA²LEN UCARE, urticaria centers have to apply and fulfill 32 requirements, defined by specific deliverables that are assessed during an audit visit.
The GA²LEN UCARE program will result in a strong network of urticaria specialists, promote urticaria research, and harmonize and improve urticaria management globally.
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