How to manage chronic urticaria 'beyond' guidelines: a practical algorithm.

Chronic urticaria (CU) is a disease characterized by pruritic weals, angio-oedema or both occurring for at least 6 weeks. It encompasses spontaneous and inducible urticarias. The national and international guidelines outline the principles of treatment. Omalizumab, an anti-immunoglobulin E monoclonal antibody, has transformed the management of many severe and treatment-refractory patients. However, current UK guidance on its use does not address the needs of those with less severe disease, inducible urticarias, idiopathic histaminergic angio-oedema without weals as a presentation of CU and omalizumab non-responders. Our algorithm and a summary of the evidence to support its principles offers guidance and a more systematic targeted approach to using a range of 'off-label' agents for specific phenotypes of CU. It will be of use when guideline-recommended mast cell mediator antagonists fail to control symptoms and/or using omalizumab is ineffective, not practical or unfunded.

The definition, diagnostic testing, and management of chronic inducible urticarias - The EAACI/GA(2) LEN/EDF/UNEV consensus recommendations 2016 update and revision.

These recommendations for the definition, diagnosis and management of chronic inducible urticaria (CIndU) extend, revise and update our previous consensus report on physical urticarias and cholinergic urticaria (Allergy, 2009). The aim of these recommendations is to improve the diagnosis and management of patients with CIndU. Our recommendations acknowledge the latest changes in our understanding of CIndU, and the available therapeutic options, as well as the development of novel diagnostic tools.

Definition, aims, and implementation of GA(2) LEN Urticaria Centers of Reference and Excellence.

BACKGROUND: 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. AIMS: Here, we describe the aims, the requirements and deliverables, the application process, and the audit and accreditation protocol for GA²LEN UCAREs. RESULTS: 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. DISCUSSION AND CONCLUSION: The GA²LEN UCARE program will result in a strong network of urticaria specialists, promote urticaria research, and harmonize and improve urticaria management globally.

EAACI taskforce position paper: evidence for autoimmune urticaria and proposal for defining diagnostic criteria.

An autoimmune subset of chronic spontaneous urticaria is increasingly being recognized internationally, based on laboratory and clinical evidence that has accrued over the last 20 years. This evidence has been reviewed by a taskforce of the Dermatology section of the European Academy of Allergy and Clinical Immunology. Functional autoantibodies in chronic urticaria (CU) patient sera have been demonstrated against IgE and FcεRIα by basophil and mast cell histamine release assays and by basophil activation assays. Antibody specificity has been confirmed by immunoassay, but there is a poor correlation between functionality and immunoreactivity. Approximately 25% of CU patients have a positive basophil histamine release assay and show autoreactivity (a positive autologous serum skin test), whereas 50% are negative regarding both. Functionality of CU sera appears to be complement dependent on mast cells but not exclusively on basophils. Basophil activation by CU sera is predominantly restricted to IgG1 and IgG3 subclasses. Circumstantial evidence for CU being an autoimmune disease comes from an observed association with other autoimmune diseases, a strong association between serum functionality and HLA-DR4 haplotype and the good response of CU patients to immunotherapies. It was proposed that a study should be undertaken to prospectively validate potentially relevant clinical criteria (from the history, examination and routinely available clinical investigations) against a new 'gold standard' for the diagnosis of ACU (positive autoreactivity, functional bioassay and immunoassay) to define preliminary criteria sets for the diagnosis of ACU based on clinical and laboratory features with highest individual sensitivity and specificity.

Unexplained recurrent fever: when is autoinflammation the explanation?

Recurrent fever can be the sole or leading manifestation of a variety of diseases including malignancies, autoimmune diseases and infections. Because the differential diagnoses are manifold, no formal guidelines for the approach of patients with recurrent fever exists. The newly recognized group of autoinflammatory diseases are often accompanied by repetitive fever attacks. As these episodes are frequently associated by a variety of divergent presentations, the differentiation of other causes for febrile illnesses can be difficult. In this article, we first review disease entities, which frequently present with the symptom of recurrent fever. In a next step, we summarize their characteristic pattern of disease presentation. Finally, we analyse key features of autoinflammatory diseases, which are helpful to distinguish this group of diseases from the other causes of recurrent fever. Recognizing these symptom patterns can provide the crucial clues and, thus, lead to the initiation of targeted specific diagnostic tests and therapies.

How not to miss autoinflammatory diseases masquerading as urticaria.

Urticarial skin reactions are one of the most frequent problems seen by allergists and clinical immunologists in daily practice. The most common reason for recurrent wheals is spontaneous urticaria. There are, however, several less common diseases that present with urticarial rash, such as urticarial vasculitis and autoinflammatory disorders. The latter include cryopyrin-associated periodic syndrome and Schnitzler's syndrome, both rare and disabling conditions mediated by increased interleukin-1 secretion. Apart from the urticarial rash, patients are suffering from a variety of systemic symptoms including recurrent fever attacks, arthralgia or arthritis and fatigue. Autoinflammatory diseases are often associated with a diagnostic delay of many years and do not respond to antihistamines and other treatments of urticaria. Also, the chronic inflammation may lead to long-term complications such as amyloidosis. It is therefore important not to miss these diseases when diagnosing and treating patients with chronic recurrent urticarial rash. Here, we present clinical clues and tips that can help to identify autoinflammatory disorders in patients presenting with chronic urticarial rash and discuss their clinical picture and management.

Unmet clinical needs in chronic spontaneous urticaria. A GA²LEN task force report.

Chronic spontaneous urticaria, formerly also known as chronic idiopathic urticaria and chronic urticaria (CU), is more common than previously thought. At any time, 0.5-1% of the population suffers from the disease (point prevalence). Although all age groups can be affected, the peak incidence is seen between 20 and 40 years of age. The duration of the disease is generally 1-5 years but is likely to be longer in more severe cases, cases with concurrent angioedema, in combination with physical urticaria or with a positive autologous serum skin test (autoreactivity). Chronic spontaneous urticaria has major detrimental effects on quality of life, with sleep deprivation and psychiatric comorbidity being frequent. It also has a large impact on society in terms of direct and indirect health care costs as well as reduced performance at work and in private life. In the majority of patients, an underlying cause cannot be identified making a causal and/or curative treatment difficult. Nonsedating H1-antihistamines are the mainstay of symptomatic therapy, but treatment with licensed doses relieves symptoms effectively in < 50% of patients. Although guideline-recommended updosing up to fourfold increases symptom control in many patients, a substantial number of patients have only little benefit from H1 -antihistamines. Consequently, there is a great need for new therapeutic strategies.

Serum total tryptase levels are increased in patients with active chronic urticaria.

BACKGROUND: We have demonstrated previously mast cell histamine release upon incubation with chronic urticaria (CU) sera, presumably by degranulation. OBJECTIVE: To explore total and mature tryptase in order to assess whether any increase in total tryptase levels is due in part to mast cell degranulation or to mast cell burden. We also wanted to explore differences between the autoimmune groups called idiopathic (serum unable to activate basophils), and to correlate total and mature tryptase levels with different urticaria features. METHODS: We measured total and mature tryptase serum levels in 81 CU patients, 16 atopic donors and 21 healthy control sera. We assessed autoimmunity by measuring the CD63 expression in normal basophil donors upon incubation with CU sera. RESULTS: We found significantly higher levels of total tryptase in the sera of CU patients (6.6 ±4.1 µg/L) than in sera from healthy non-atopic subjects (4.4 ±2.8 µg/L) and from atopic subjects (4.5 ±1.7 µg/L). Mature tryptase levels were undetectable (<1 ng/mL). Total tryptase levels in the autoimmune urticaria group were significantly higher (9.8 ±5.4 µg/L) than the idiopathic urticaria group (4.4 ±2.2 µg/L). A significant difference in total tryptase was found between symptomatic patients (7.3 ±4.1 µg/L) compared with asymptomatic ones (5.7 ±4.1 µg/L) at the time of venesection. No difference was found in mature tryptase levels either. CONCLUSION: Total elevated tryptase levels are not accompanied by an elevated mature tryptase levels, as might be expected if the serum levels reflected mast cell degranulation.

Methotrexate: a useful steroid-sparing agent in recalcitrant chronic urticaria.

Background Reports of methotrexate for chronic urticaria are anecdotal. Objectives To assess the effectiveness of methotrexate in steroid-dependent chronic urticaria, its impact on steroid reduction and any differences in response between patients with and without functional autoantibodies. Methods A retrospective case-note review of 16 patients with steroid-dependent chronic urticaria treated with methotrexate was carried out. Ten patients had chronic ordinary/spontaneous urticaria (CU), including three with associated delayed-pressure urticaria; four patients had normocomplementaemic urticarial vasculitis (UV); and two patients had idiopathic angio-oedema without weals. Median disease duration before methotrexate was 48.5 months (range 12-164). All were unresponsive to antihistamines and second-line agents, except prednisolone. Eleven were assessed for autoimmune urticaria with the basophil histamine release assay (n = 5), autologous serum skin test (n = 5) or both (n = 1). Response to methotrexate was scored: no benefit; some benefit (fewer weals and symptomatic improvement but no steroid reduction); considerable benefit (improvement with steroid reduction); or clear (no symptoms, off steroids but on antihistamines). Results Twelve of 16 patients (eight CU, three UV, one idiopathic angio-oedema) responded. Three showed some benefit, seven considerable benefit and two cleared. Four of eight responders and three out of three nonresponders showed evidence of functional autoantibodies. The dose to achieve a steroid-sparing effect was 10-15 mg weekly (cumulative dose range 15-600 mg, median 135 mg). Methotrexate was well tolerated. Conclusions Methotrexate may be a useful treatment for steroid-dependent chronic urticaria. Functional autoantibodies do not correlate with response. The beneficial effects of methotrexate may be anti-inflammatory and immunosuppressive. It may therefore benefit chronic urticaria independently of the pathogenic mechanism, whether autoimmune or not.

Correction to: Highlights and recent developments in skin allergy and related diseases in EAACI journals (2018).

[This corrects the article DOI: 10.1186/s13601-019-0299-y.].

Highlights and recent developments in allergic diseases in EAACI journals (2019).

The European Academy of Allergy and Clinical Immunology (EAACI) owns three journals: Allergy, Pediatric Allergy and Immunology and Clinical and Translational Allergy. One of the major goals of EAACI is to support health promotion in which prevention of allergy and asthma plays a critical role and to disseminate the knowledge of allergy to all stakeholders including the EAACI junior members. There was substantial progress in 2019 in the identification of basic mechanisms of allergic and respiratory disease and the translation of these mechanisms into clinics. Better understanding of molecular and cellular mechanisms, efforts for the development of biomarkers for disease prediction, novel prevention and intervention studies, elucidation of mechanisms of multimorbidities, entrance of new drugs in the clinics as well as recently completed phase three clinical studies and publication of a large number of allergen immunotherapy studies and meta-analyses have been the highlights of the last year.

EAACI/GA(2)LEN task force consensus report: the autologous serum skin test in urticaria.

Injection of autologous serum collected during disease activity from some patients with chronic spontaneous urticaria (CU) into clinically normal skin elicits an immediate weal and flare response. This observation provides a convincing demonstration of a circulating factor or factors that may be relevant to the understanding of the pathogenesis and management of the disease. This test has become known as the autologous serum skin test (ASST) and is now widely practised despite incomplete agreement about its value and meaning, the methodology and the definition of a positive response. It should be regarded as a test for autoreactivity rather than a specific test for autoimmune urticaria. It has only moderate specificity as a marker for functional autoantibodies against IgE or the high affinity IgE receptor (FcepsilonRI), detected by the basophil histamine release assay, but high negative predictive value for CU patients without them. It is usually negative in other patterns of CU, including those that are physically induced. Positive ASSTs have been reported in some subjects without CU, including those with multiple drug intolerance, patients with respiratory allergy and healthy controls, although the clinical implications of this are uncertain. It is essential that failsafe precautions are taken to ensure that the patient's own serum is used for skin testing and aseptic procedures are followed for sample preparation and handling. CU patients with a positive ASST (ASST(+)) are more likely to be associated with HLADR4, to have autoimmune thyroid disease, a more prolonged disease course and may be less responsive to H1-antihistamine treatment than those with a negative ASST (ASST(-)) although more evidence is needed to confirm these observations conclusively.

The definition and diagnostic testing of physical and cholinergic urticarias--EAACI/GA2LEN/EDF/UNEV consensus panel recommendations.

The recommendations for the definition and diagnosis presented in this position paper are the result of a panel consensus meeting held in December 2008 in Berlin. This consensus meeting was a joint initiative of EAACI (European Academy of Allergology and Clinical Immunology) Dermatology Section, the EU-funded network of excellence, GA(2)LEN (Global Allergy and Asthma European Network), the EDF (European Dermatology Forum) and UNEV (urticaria network e.V.). The aim of these recommendations is to improve the diagnosis and management of patients with physical urticaria or cholinergic urticaria and to promote research and a better understanding of these diseases. Our recommendations used the paper produced by a 1996 expert meeting (1) and they acknowledge the latest changes in our understanding of physical urticarias and cholinergic urticaria as well as the recent development of novel diagnostic tools. In addition, this consensus paper highlights areas of need for further research.

EAACI/GA(2)LEN/EDF/WAO guideline: definition, classification and diagnosis of urticaria.

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/GA(2)LEN/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 (GA(2)LEN), 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).

EAACI/GA(2)LEN/EDF/WAO guideline: management of urticaria.

This guideline, together with its sister guideline on the classification of urticaria (Zuberbier T, Asero R, Bindslev-Jensen C, Canonica GW, Church MK, Giménez-Arnau AM et al. EAACI/GA(2)LEN/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 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 (GA(2)LEN), 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 H(1)-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 H(1)-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).