An international Delphi study on the burden of allergic rhinoconjunctivitis and urticaria and the role of bilastine among current treatment options.

BACKGROUND: Allergic rhinoconjunctivitis and chronic urticaria are common histamine-driven diseases, exerting detrimental effects on cognitive functions, sleep, daily activities, and quality of life. Non-sedating second-generation H1-antihistamines are the first-line treatment of choice. Aim of the study was to define the role of bilastine among second-generation H1-antihistamines in the treatment of allergic rhinoconjunctivitis and urticaria in patients of different ages. METHODS: An international Delphi study was carried out to assess consensus among experts from 17 European and extra-European countries on three main topics: 1) Burden of disease; 2) Current treatment options; 3) Specific characteristics of bilastine among second-generation antihistamines. RESULTS: Here, we present the results obtained for a selection of 15 out of 27 consensus statements, focused on disease burden, role of second-generation antihistamines and bilastine profile. The rate of concordance was ≥98% for 4 statements, ≥ 96% for 6, ≥ 94% for 3, and ≥90% for 2. CONCLUSIONS: The high degree of agreement obtained suggests a wide awareness of the burden of allergic rhinoconjunctivitis and chronic urticaria among experts from all over the world and reflects a broad consensus on the role of second-generation antihistamines in general and of bilastine in particular for their management.

Interleukin-17 is a potential player and treatment target in severe chronic spontaneous urticaria.

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.

Characterization of cowhage-induced pruritus in inflamed and non-inflamed skin.

BACKGROUND AND OBJECTIVE: Pruritus is a major symptom of many inflammatory diseases and impacts greatly the quality of life in patients. We aimed to specify the characteristics of experimentally induced pruritus in normal skin and in experimentally induced inflammatory dermatitis in healthy volunteers. METHODS: Skin inflammation was induced by the repeated application of sodium lauryl sulphate (SLS 2%) on the volar forearms of 30 healthy volunteers. Inflammatory dermatitis intensity was assessed using the eczema score adapted from Frosch and Kligman. Non-histaminergic pruritus was induced by cowhage spicules rubbed on the volar forearms and recorded for 30 min on a 10-cm visual analogue scale (VAS) in both non-inflamed and inflamed skin. RESULTS: Induction of inflammatory dermatitis by SLS resulted in a mild inflammatory dermatitis with an inflammation score of 2.3 ± 0.1 within 7 days of treatment. Cowhage-induced pruritus was of markedly higher intensity (P < 0.001), and all but two individuals had higher maximum pruritus intensity in inflamed skin as compared to non-inflamed skin, whereas the kinetics of the pruritus response were similar. The quality of cowhage-induced pruritus was significantly different with more 'burning' and 'painful sensations' in inflamed skin (P < 0.01). Maximum pruritus intensity in inflamed skin strongly correlated with maximum pruritus intensity in non-inflamed skin (r = 0.51, P = 0.004). Skin hydration, skin barrier integrity and dermatitis severity did not correlate with pruritus intensity. CONCLUSION: Taken together, pruritus in inflamed skin is perceived as more intense, painful and burning. This may explain, in part, why pruritus is a major driver of quality-of-life impairment in patients with chronic inflammatory skin conditions such as atopic dermatitis.

Comparison of pruritus and sensory qualities induced by capsaicin, histamine and cowhage.

BACKGROUND: In skin diseases and experimental models of pruritus, pure itch is accompanied by additional sensations that are poorly characterized. OBJECTIVES: This study compared the sensory qualities evoked by different models of experimentally induced pruritus including skin prick testing (SPT) with histamine or capsaicin and application of cowhage spicules. SPT as a method of capsaicin application was validated for this purpose. METHODS: Two pilot experiments were performed in eight healthy volunteers. First, a concentration of 8% capsaicin was identified as evoking a reproducible itch using SPT. Further, a list of the seven most frequently reported sensations was chosen after SPT with 10 mg/mL histamine, 8% capsaicin and application of 40-45 cowhage spicules. Finally, 31 subjects were challenged with the same itch-inducers. Wheal and flare were measured at 10, 20, 40, 60 and 90 min, itch intensity every minute for 30 min, and the overall evaluation of sensory descriptors were recorded on a 100-mm visual analogue scale once itching had subsided. RESULTS: Skin prick testing with histamine and capsaicin resulted in flare reactions, which were 23% smaller for capsaicin (P < 0.001). Histamine, capsaicin and cowhage-induced pruritus, the duration of which was shorter for cowhage than for histamine (13.5 ± 1.4 vs. 8.8 ± 1.2 min, P = 0.005). Different mediators induced sensations of different intensities. Capsaicin produced less itch and physical urge to scratch than histamine (P = 0.001) and cowhage (P < 0.001). However, both capsaicin and cowhage induced more burning than histamine (P = 0.002 and P = 0.04, respectively). Provocation with cowhage caused more intense sensations of pricking than histamine (P = 0.033). CONCLUSION: This study shows that provocation with histamine, capsaicin and cowhage results in itch responses that are different in their duration, the profile of accompanying sensations, and the flare that comes with the itch.

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.

This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded 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 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. 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.

Bilastine: a new H1 -antihistamine with an optimal profile for updosing in urticaria.

This review set out to examine published papers detailing the efficacy of bilastine in skin models and urticaria to assess whether it meets the optimal profile for updosing in urticaria, that is, strong clinical efficacy and freedom from unwanted side effects, particularly sedation. Bilastine is a highly effective H1 -antihistamine even when used at the basic dose of 20 mg daily. Its facilitated uptake after oral dosage gives it a rapid onset and long duration of action. In both wheal and flare studies and in urticaria updosing fourfold showed increased effectiveness. With respect to somnolence, bilastine is a substrate for P-glycoprotein, a membrane pump which prevents it crossing the blood-brain barrier. Consequently, bilastine is a practically 'non-sedating' H1 -antihistamine. In conclusion, the excellent profile of bilastine in both efficacy and safety make it the ideal H1 -antihistamine for updosing the daily dose fourfold in difficult-to-treat urticaria as recommended by the EAACI/GA2 LEN/EDF/WAO guideline for the management of urticaria.

Potential blood biomarkers in chronic spontaneous urticaria.

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.

Skin provocation tests may help to diagnose atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is a common skin disorder. Its diagnosis relies on clinical judgment. Mild and untypical manifestations may cause diagnostic difficulties. Biomarkers for the differential diagnostic workup of AD are needed. OBJECTIVE: To test whether the results of skin provocation with cowhage, an established model of histamine-independent pruritus, and histamine are different in AD patients and healthy subjects and whether these tests may be used as diagnostic markers of AD. METHODS: Twenty-two AD patients and 18 healthy controls were subjected to topical cowhage provocation and skin prick testing with histamine and assessed for differences in the quality, intensity, and persistence of itch, for wheal diameter, volume, and flare size and intensity. RESULTS: Patients with AD, compared with healthy controls, exhibited significantly smaller histamine-induced flares (P < 0.01) and markedly longer itch persistence after provocation with cowhage (P < 0.01). Both parameters showed good diagnostic properties for AD (area under the receiver operating characteristic (ROC) curve 0.78 and 0.80, respectively). The persistence of cowhage-induced itch for at least 30 min and a histamine-induced flare of less than 2 cm in diameter were reliable thresholds for the diagnosis of AD. If combinations of the results of both tests were used, their sensitivity and specificity of diagnosing AD were up to 91% and 94%, respectively. CONCLUSION: The clinical benefit of cowhage and histamine skin provocation tests should be investigated in further studies. Long persistence of cowhage-induced itch and diminished histamine-induced flare in nonlesional skin may support diagnosis of AD.

Atopic predisposition in cholinergic urticaria patients and its implications.

BACKGROUND: Cholinergic urticaria (CholU) is a frequent chronic urticaria disorder with itchy weal and flare-type skin reactions in response to physical exercise or passive warming. A higher frequency of atopy among CholU patients has been reported, but the significance of this observation is unclear. OBJECTIVE: To assess the prevalence and relevance of atopy in CholU patients. MATERIALS AND METHODS: Thirty CholU patients were assessed for atopic skin diathesis (atopic predisposition) by use of the Erlangen Atopy Score and divided into atopic and non-atopic predisposed CholU individuals. Both groups were assessed for disease severity (CholUSI) and activity (CholUAS7), quality of life impairment [Dermatology Life Quality Index (DLQI) and CU-Q2 OL], seasonal exacerbation, total and specific serum IgE and comorbidities. RESULTS: CholU patients were found to exhibit high rates of atopic predisposition (57%), with higher prevalence and scores in female than in male patients. High Erlangen Atopy Scores were linked to high CholU severity, activity and impact on QoL. Atopic predisposed CholU patients show different seasonal exacerbation patterns, IgE specificity and comorbidity profiles as compared to non-atopic CholU patients. CONCLUSION: Atopic predisposition and cholinergic urticaria appear to be linked more closely than previously thought, which suggests shared pathogenetic mechanisms. Atopic patients with cholinergic urticaria have more severe disease and poorer quality of life than those who do not. Thus, all cholinergic urticaria patients should be assessed for atopic predisposition.

Questions and answers in chronic urticaria: where do we stand and where do we go?

This supplement reports proceedings of the second international Global Urticaria Forum, which was held in Berlin, Germany in November 2015. In 2011, a report of the GA(2) LEN task force on urticaria outlined important and unanswered questions in chronic urticaria (CU). These included, but were not limited to, questions on the epidemiology and course of chronic spontaneous urticaria (CSU) [also called chronic idiopathic urticaria (CIU)], the resources allocated for the diagnosis and treatment of CSU, whether patients with angioedema as an isolated symptom can be regarded as a subgroup of CSU, and the efficacy and long-term safety of therapies. Many of these questions have been addressed by recent studies. Some of the answers obtained raise new questions. Here, we summarize some of the key insights on CU obtained over recent years, and we discuss old and new unmet needs and how to address them with future studies. We need to analyze the influence of recent advances in understanding of the burden of CU on patients and society, disease management and the CU patient journey. Our increased understanding of urticarial pathophysiology and consideration of the patient as a whole will need to be translated to better treatment algorithms and protocols. Actions to address these challenges include the 5th International Consensus Meeting on Urticaria, which will take place later this year. The formation of a global network of Urticaria Centers of Reference and Excellence over the next few years has also been proposed, with the aim of providing consistent excellence in urticaria management and a clear referral route, furthering knowledge of urticaria through additional research and educating/promoting awareness of urticaria.

Histamine intolerance in patients with chronic spontaneous urticaria.

BACKGROUND: Histamine intolerance and pseudoallergy to foods have been suggested to be causes of chronic spontaneous urticaria (CSU) with some patients reporting exacerbation with histamine-rich foods. OBJECTIVE: The study aim was to identify the rate of histamine-intolerant CSU patients and to characterize the relevance of histamine intolerance as an underlying cause of CSU. METHODS: A cohort of 157 of moderate to severe CSU patients (UAS7 ≥ 10) was asked to provide a detailed clinical history, particularly in relation to symptom development after eating histamine-rich foods. They subsequently undertook a histamine-free pseudoallergen-low diet followed by a double-blind, placebo-controlled oral histamine provocation (75 mg). RESULTS: One third of patients (34%) had a positive history of histamine intolerance. There was no statistical difference between the mean UAS7 scores of patients with positive and negative histories (22.4 ± 1.0 vs. 22.7 ± 0.8). When kept on diet, 46% of patients responded with reduced CSU activity (UAS7 reduction of ≥7). Following double-blind, placebo-controlled oral histamine provocation, 17% of patients gave a positive weal response. There appeared to be little relationship between patient history, response to diet and the weal response to oral histamine provocation. First, the history-positive and -negative groups contained similar proportions of diet and histamine provocation weal-positive patients. Second, the diet-positive and -negative groups contained similar proportions of history-positive and histamine provocation weal-positive patients. Third, the histamine provocation weal-positive and -negative groups had similar rates of history- and diet-positive patients. Finally, only 2 of the 157 patients were positive in all three domains. CONCLUSIONS: CSU due to histamine intolerance appears to be rare and cannot be diagnosed based on the history. The study confirms that avoidance diets low in pseudoallergens can improve urticaria symptoms, this is probably not due to the absence of dietary histamine.

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.

Development and validation of the mastocytosis quality of life questionnaire: MC-QoL.

BACKGROUND: Mastocytosis is a heterogeneous disease characterized by a clonal expansion of mast cells in various organs. The vast majority of patients affected suffer from signs and symptoms caused by mediator release from mast cells. Although the disease burden is high, there is currently no specific instrument to measure health-related quality of life (HRQoL) impairment in patients with mastocytosis. OBJECTIVE: The aim of this study was to develop and validate a disease-specific tool to assess HRQoL impairment in patients with cutaneous and indolent systemic mastocytosis, the Mastocytosis Quality of Life Questionnaire (MC-QoL). METHODS: Sixty-two potential MC-QoL items were developed in a combined approach consisting of semi-structured patient interviews, expert input and literature research. Item selection was performed by impact analysis with 76 patients and a final review for face validity. The resulting MC-QoL was tested for validity, reliability and influence factors. In parallel, an US American-English version of the MC-QoL was developed. RESULTS: A total of 158 patients (41 CM, 41 MIS and 76 ISM) took part in the MC-QoL validation study. The final 27-item questionnaire was found to have a four-domain structure ('symptoms', 'emotions', 'social life/functioning' and 'skin'), a valid total score and an excellent test-retest reliability. Multiple regression analysis revealed disease duration, but not age, gender or skin involvement to be a significant determinant of HRQoL impairment in mastocytosis. CONCLUSIONS: The MC-QoL is the first disease-specific HRQoL questionnaire for adult patients with cutaneous and indolent systemic mastocytosis. This short, validated and reliable instrument will serve as a valuable tool in future clinical studies and in routine patient care.

Management and treatment of chronic urticaria (CU).

Developments increasing our understanding of chronic urticaria have resulted in the simplification and improvement of available treatments. Currently, many treatments target mast cell mediators, but we can now disrupt mast cell activation with the anti-IgE antibody omalizumab, which has markedly advanced the treatment landscape for patients with difficult-to-treat urticaria. Current guidelines provide a framework for the management and treatment of patients with CU but, as each patient is different, knowledge and experience of specialist dermatologists and allergists are key to effective pharmacotherapy. This article reviews the different therapeutic options for patients with chronic spontaneous urticaria (also called chronic idiopathic urticaria) or chronic inducible urticaria and discusses management of special populations or special circumstances related to CU.

An improved Peltier effect-based instrument for critical temperature threshold measurement in cold- and heat-induced urticaria.

BACKGROUND: Cold- and heat-induced urticaria are chronic physical urticaria conditions in which wheals, angioedema or both are evoked by skin exposure to cold and heat respectively. The diagnostic work up of both conditions should include skin provocation tests and accurate determination of critical temperature thresholds (CTT) for producing symptoms in order to be able to predict the potential risk that each individual patient faces and how this may be ameliorated by therapy. OBJECTIVE: To develop and validate TempTest(®) 4, a simple and relatively inexpensive instrument for the accurate determination of CTT which may be used in clinical practice. METHODS: TempTest(®) 4 has a single 2 mm wide 350 mm U-shaped Peltier element generating a temperature gradient from 4 °C to 44 °C along its length. Using a clear plastic guide placed over the skin after provocation, CTT values may be determined with an accuracy of ±1 °C. Here, TempTest(®) 4 was compared with its much more expensive predecessor, TempTest(®) 3, in inducing wheals in 30 cold urticaria patients. RESULTS: Both TempTest(®) 4 and TempTest(®) 3 induced wheals in all 30 patients between 8 ° and 28 °C. There was a highly significant (P < 0.0001) correlation between the instruments in the CTT values in individual patients. CONCLUSION: The TempTest(®) 4 is a simple, easy to use, licensed, commercially available and affordable instrument for the determination of CTTs in both cold- and heat-induced urticaria.

Omalizumab may not inhibit mast cell and basophil activation in vitro.

BACKGROUND: In March 2014, omalizumab, a monoclonal anti-IgE antibody, was approved for the treatment of chronic spontaneous urticaria (CSU). The primary mode of action of omalizumab is considered to be the reduction in free IgE serum levels and the subsequent down-regulation of FcεRI, the high affinity receptor for IgE, on mast cells and basophils. Recently, it has been suggested that most CSU patients have an autoimmune aetiology which may lead to chronic activation of mast cells and basophils. OBJECTIVE: To understand more of the mechanisms by which omalizumab may exert its effects in CSU, its efficacy was tested on human mast cells and basophils. METHODS: Omalizumab, which was or was not preincubated with serum from healthy donors or CSU patients, was coincubated with isolated healthy donor skin mast cells or peripheral blood-derived monocytes containing 1-2% basophils. Degranulation was induced using anti-human IgE, C5a, or substance P and histamine release determined. RESULTS: Anti-human IgE-induced histamine release from mast cells or basophils was not altered in the presence or absence of omalizumab. In contrast, preincubation of mast cells with DARPin Fc fusion protein, a positive control for negative signalling via FcεRI-FcγRIIb cross activation, significantly diminished histamine release. Moreover, omalizumab, that was preincubated with healthy donor serum, CSU patient serum or auto-reactive CSU serum to allow for the formation of potential immune complexes, did not alter induced histamine release in a coincubation setup with mast cells or basophils as compared to the absence of omalizumab. In vivo, blood basophil numbers and basophil histamine content increase under omalizumab therapy. CONCLUSION: Our results suggest that the rapid response to omalizumab therapy is more likely to result from the elimination of an activating signal rather than the generation of a negative, inhibitory signal.