Epidemiology, comorbidities, and healthcare utilization of patients with chronic urticaria in Germany.

BACKGROUND: Comprehensive data on the epidemiology and comorbidities of chronic urticaria (CU) in Germany are either limited, or not contemporary. OBJECTIVES: To investigate the epidemiology of CU, overall comorbidities and healthcare resource utilized by patients with CU in Germany, using an anonymized statutory health insurance (SHI) database. METHODS: Anonymized SHI claims research database of the Institute for Applied Health Research, Berlin [InGef] (01 January 2015-30 September 2018) was used to analyse insured individuals with a confirmed diagnosis of CU (ICD-10-GM codes). Twelve-month diagnosed prevalence and incidence, comorbidities (vs. atopic dermatitis and psoriasis), and healthcare utilization by patients with CU were investigated. RESULTS: Of 4 693 772 individuals of all ages listed in the database, 3 538 540 were observable during 2017. Overall, 17 524 patients (˜0.5%) were diagnosed with CU; chronic spontaneous urticaria (CSU: 71.2%), chronic inducible urticaria (CIndU: 19.7%), CSU+CIndU (9.1%). Females, vs. males, had higher diagnosed prevalence (0.62% vs. 0.37%) and diagnosed incidence (0.18% vs. 0.11%) of CU among all patients. Patients most frequently visited general practitioners (41.3% of total visits). Hypertensive diseases (43.5%), lipoprotein metabolism disorders (32.1%) and affective disorders (26.0%) were the most frequently reported comorbidities of special interest. Rates of most comorbidities of special interests were similar to atopic dermatitis and psoriasis patients, and all higher vs. overall population. More than half (54.1%) of all CU patients were not prescribed any treatment. Second-generation H1 -antihistamines were the most commonly prescribed medication for adult (17.9%) and paediatric (27.9%) patients. Patients with CIndU (paediatric, 15.5%; adult, 7.8%) were more often hospitalized versus patients with CSU (paediatric, 9.9%; adult, 4.6%). CONCLUSIONS: In Germany, prevalence of CU along with multiple comorbidities may pose increased burden on the healthcare system. Awareness of adhering to treatment guidelines, and aiming for complete control of urticaria, needs to be driven and may improve outcomes.

Lanadelumab to treat hereditary angioedema.

Lanadelumab is a human monoclonal antibody against plasma kallikrein indicated for prevention of attacks of hereditary angioedema (HAE). HAE is caused by SERPING1 gene mutations resulting in decreased or dysfunctional plasma protease C1 inhibitor (C1-INH) leading to a loss of inhibition of plasma kallikrein activity with subsequent cleavage of high-molecular weight kininogen and release of bradykinin. There is a clear need for a non-plasma-derived, safe, effective and convenient prophylaxis of HAE attacks to reduce patients' daily burden of disease and disability. The percentage of patients who were attack-free for the last 16 weeks of a controlled study was 77% in the group receiving 300 mg lanadelumab every 2 weeks, compared with 3% with placebo. The most common side effects were mild injection-site reactions. Lanadelumab has the potential to change the approach from on-demand treatment to prophylaxis in HAE. Future studies will have to confirm long-term safety and efficacy of prophylactic long-term inhibition of plasma kallikrein.

[Gender aspects in angioedema]. / Genderaspekt bei Angioödemen.

BACKGROUND: Angioedema can be triggered by mediators bradykinin or histamine. Gender-specific differences and potential biomarkers for follow-up/therapy monitoring are mostly unknown. OBJECTIVES: To what extent are gender-related defects, prodromes, trigger factors, clinical parameters such as number of attacks, frequency, localization, laboratory values, hormones and response to therapy different for the variant types of angioedema. MATERIALS AND METHODS: A literature search was performed in PubMed with the keywords "angioedema" and "sex" or "gender" as well as targeted screening of reviews, guidelines and registration studies with angioedema-relevant drugs. RESULTS: In histamine-mediated angioedema, there are few gender-specific differences. In bradykinin-mediated hereditary angioedema, especially with factor XII mutation, but also in angiotensin-converting enzyme inhibitor-induced angioedema, women are more frequent, more affected and hormonal influences are documented. The localization of bradykinin-mediated hereditary angioedema (HAE) is also gender specific. The proportion of women in clinical trials for HAE therapies is about two-thirds. CONCLUSION: Principally, differentiating between estrogen-dependent, estrogen-sensitive and estrogen-insensitive angioedema seems reasonable. The characterization of these subgroups may lead to a better understanding of the pathomechanism of the hormone effects on angioedema. This could lead to the development of urgently needed biomarkers for faster and more targeted diagnosis and prediction of attacks, to significantly improve the health and quality of life of angioedema patients by means of individualized gender-specific therapy.

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.

National clinical practice guidelines for allergen immunotherapy: An international assessment applying AGREE-II.

BACKGROUND: Since 1988, numerous allergen immunotherapy guidelines (AIT-GLs) have been developed by national and international organizations to guide physicians in AIT. Even so, AIT is still severely underused. OBJECTIVE: To evaluate AIT-GLs with AGREE-II, developed in 2010 by McMaster University methodologists to comprehensively evaluate GL quality. METHODS: Allergist, from different continents, knowledgeable in AIT and AGREE-II trained were selected into the project team. The project received methodologists' guidance. AIT-GLs in any language were sought from 1980 to 2016; AIT-GLs were AGREE II-evaluated by at least 2 team members, independently; discrepancies were resolved in a second round, by team discussion or methodologists' consulting. RESULTS: We found 31 AIT-GLs (15 post-2010), ranging from local consensus reports to international position papers (EAACI, AAAAI-ACAAI, WAO). Pre-2010 GLs scored 1.6-4.6 (23%-67%) and post-2010 GLs scored 2.1-6 (30%-86%), on a 7-point Likert scale. The highest scores went to: German-Austrian-Swiss (6.0), Mexican (5.1), and the AAAAI/ACAAI AIT-GL (4.7). These were also the only 3 GLs that received "yes" of both evaluators to the item: "I would recommend this GL for use." The domains of "Stakeholder involvement" and "Rigor of Development" only scored 3/7, and "Applicability" scored the lowest. Strikingly, newer GLs only scored clearly better in "Editorial independence" and "Global evaluation." CONCLUSIONS: In AIT-GLs, there is still a lot of room for improvement, especially in domains crucial for the dissemination. For some GLs, the "Scientific rigor" domain flawed. When resources are limited, transculturizing a high-quality GL might be preferable over developing a GL from zero. Our study and AGREE-II could help to select the best candidate. CLINICAL IMPLICATIONS: We here evaluate allergen immunotherapy guideline (AIT-GL) quality. Only high-quality AIT-GLs should be consulted for AIT management decisions. In low-resource settings, transculturization of these is preferred over developing low-quality guidelines.

[Placebo effect in clinical trials with allergen-specific immunotherapy with inhalant allergens]. / Placeboeffekt in Studien zur allergenspezifischen Immuntherapie mit Inhalationsallergenen.

Placebo effects play an important role in the treatment of allergic diseases. Therefore, in this study, we analysed the described effects of placebo in all double-blind placebo-controlled clinical trials of allergen-specific immunotherapy (ASIT) with inhalant allergens (birch, grass, house dust mites) listed in the tables (updated July 2016) attached to the German S2k guideline on allergen-specific immunotherapy in IgE-mediated allergic diseases. The most common placebo consisted of verum without allergen, but when the subcutaneous route was used, histamine was sometimes added. From the 33 studies analysed no conclusions could be drawn regarding the pure placebo effect. The symptom medication score (SMS) from an adequate baseline period was described in one single study. An untreated population was not included in any study. Indirect evidence points to substantial placebo effects in up to 77% of the subjects with respect to retrospective, subjective parameters. Well-known factors influencing the placebo effect such as age, gender, application route/composition of the placebo, individual and cultural differences, severity of symptoms at the beginning and the probability of receiving verum have not been addressed regarding ASIT and could not be estimated from available data. Taken together regarding ASIT the placebo effect has been investigated inadequately. In spite of significant expenditure of time and costs future ASIT studies should include assessment of the SMS in an adequate baseline period and preferably include an untreated trial arm. A better understanding of placebo effects in ASIT trials will improve the design of clinical trials and the assessment of therapeutic effects.

Food-induced anaphylaxis and cofactors - data from the anaphylaxis registry.

Food allergens are frequent causes of anaphylaxis. In particular in children and adolescents they are the most frequent elicitors of severe allergic reactions, and in adults food allergens rank third behind insect venom and drugs. Since July 2006 severe allergic reactions from Germany, Austria, and Switzerland are collected in the anaphylaxis registry. Currently 78 hospitals and private practises are connected. From July 2006 until February 2009 1,156 severe allergic reactions were registered. Among children and adolescents (n = 187, age range from 3 months to 17 years) food allergens were the most frequent triggers, comprising 58% of cases. In the adult group (n = 968, 18 - 85 years) food allergens were in the third position (16.3%) behind insect venom and drugs. In children legumes (31%) and in particular peanuts were frequently responsible food allergens, followed by tree nuts (25%) with hazelnut being the most frequent elicitor. In adults fruits (13.4%) most often induced severe food-dependent anaphylaxis, but also animal products (12.2%); among these most frequently crustaceans and molluscs. Cofactors were often suspected in food-dependent anaphylaxis, namely in 39% of the adult group and in 14% of the pediatric group. In adults drugs (22%) and physical activity (10%) were reported to be the most frequent cofactors, in children physical activity was suspected in 8.7% and drugs in 2.6%. Concomitant diseases like atopic dermatitis, allergic asthma, or allergic rhinoconjunctivitis were reported in 78% of children and adolescents and in 67% of the adults. In conclusion, food-induced anaphylaxis, its cofactors and concomitant diseases are age-dependent. The data offers to identify risk factors of anaphylaxis.

Hyperresponsiveness to antihistamines in spontaneous urticaria and heat urticaria.

. BACKGROUND: H1 antihistamines are important drugs for the treatment of urticaria and are commonly well tolerated. Cases of hypersensitivity reactions to antihistamines have rarely been reported, the underlying pathomechanism is unknown yet. CASE REPORT: We report the case of a 28-year-old female patient suffering from chronic spontaneous urticaria who experienced severe episodes of wheals and flares induced by different H1 antihistamines. METHODS: We performed skin prick tests (SPT) with a diversity of H1 antihistamines and CAST and FlowCAST analyses. Moreover, a placebo controlled oral challenge test to mizolastin was done. RESULTS: We saw positive SPT reactions to nearly all H1 antihistamines tested with the exception of mizolastin. We observed neither a release of sulfidoleukotrienes nor an upregulation of basophil activation markers in the CAST and FlowCAST analyses. The oral challenge test with mizolastine resulted in the development of generalized wheals and flares. CONCLUSION: H1 antihistamines are effective drugs for the treatment of urticaria, but they may lead to hypersensitivity reactions in rare cases. Because of the negative CAST and FlowCAST results, an IgE-mediated pathomechanism is improbable. We propose that hypersensitivity reactions to H1 antihistamines may be induced by a paradox H1 receptor activation.

[Intolerance of specific immunotherapy with Hymenoptera venom: jumping the hurdle with omalizumab]. / Unverträglichkeit der spezifischen Immuntherapie mit Hymenopterengift: Mit Omalizumab die Hürde nehmen.

Specific immunotherapy is a very effective and well-tolerated therapeutic option in patients with Hymenoptera venom allergy. Many patients can be successfully treated, and severe side-effects are rarely seen. In most cases local swelling of the injection site is noticed, whereas systemic reactions are uncommon. No reliable biomarkers to prove the positive response to the specific immunotherapy have been validated. But on the other hand the failure of the venom immunotherapy can be verified by performing a sting challenge test; in this case the maintenance dose of the venom immunotherapy has to be increased and the sting challenge test has to be repeated. This approach works well most of the patients. In rare cases severe anaphylactic reactions occur during the initiation of the venom immunotherapy due to individual risk factors. While in the past this necessitated discontinuation of the specific immunotherapy, the current situation has remarkably changed. Since the IgE-antibody omalizumab has been licensed for different indications, a new therapeutic option is available. We have employed this approach since 2005. We share our own practical experience as well as recent data, presenting a management approach for Hymenoptera venom allergy in high-risk patients.

Methods report on the development of the 2013 revision and update of the EAACI/GA2 LEN/EDF/WAO guideline for the definition, classification, diagnosis, and management of urticaria.

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 (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. 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.

The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, classification, diagnosis, and management of urticaria: the 2013 revision and update.

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).

[Urticaria. Sometimes IgE-mediated?]. / Urtikaria. Manchmal doch IgE-vermittelt?

There are specific diagnostic recommendations for approaching chronic spontaneous urticaria, physical urticaria and special forms of urticaria. They include the detection of subclinical viral and bacterial infections, particularly with Helicobacter pylori. Frequently an autoimmune urticaria is diagnosed by using the autologous serum test. Less specific findings, such as leukocytosis and elevated CRP can sometimes be helpful in suggesting subclinical infections as the cause of acute urticaria; usually no further procedures are recommended. However, in cases with a long history of intermittent attacks, particularly with severe and generalized symptoms, it is recommended to look for IgE-mediated reactions (e.g. alpha-Gal, Omega-5-Gliadin). In our hands at the Department of Dermatology and Allergy at the Hannover Medical School a standardized set of diagnostic procedures was successfully established, and is now individually completed with selected single allergens and allergen components.

[Urticaria and treatment fails]. / Urtikaria und die Therapie versagt!

According to the guidelines the treatment goal for all types of urticaria is to achieve complete symptom relief. Therefore the available literature for urticaria treatment was reviewed regarding this aim and treatment failure, respectively. Systematic studies are not available. Standard doses of H1-antihistamines are the only approved therapy. Review of the limited data where statements are made about complete alleviation of symptoms shows that standard doses of H1-antihistamines rarely achieve this. Even when the dosage is increased up to four-fold, the failure rate is high. Additional therapy with montelukast, dapsone, and cyclosporine A also often fails to produce complete control. For severe chronic spontaneous urticaria, controlled studies using omalizumab have shown low failure rates over long time periods. It has not been investigated whether up-dosing or reduced injection intervals could further improve this rate. Taken together, the small amount of available data on complete symptom relief in urticaria treatment is astonishing. Moreover, the studies can not be compared due to different inclusion criteria (severity of urticaria, allowed basic treatment) and evaluated parameters. Further controlled studies are vitally needed to achieve the goal of complete symptom relief in urticaria.

Randomized, double-blind, placebo-controlled study of safety and efficacy of miltefosine in antihistamine-resistant chronic spontaneous urticaria.

BACKGROUND: Chronic spontaneous urticaria (CSU), a mast cell-driven condition, is debilitating, common, and hard to treat. Miltefosine, a lipid raft modulator, can inhibit mast cell responses in vivo. OBJECTIVE: To study the safety and efficacy of systemic miltefosine treatment in CSU patients resistant to standard-dosed antihistamines. METHODS: In this investigator-initiated multicentre, randomized, double-blind, placebo-controlled study, CSU patients were treated for 4 weeks with daily doses of up to 150-mg miltefosine (n = 47) or placebo (n = 26). Disease activity was assessed using the urticaria activity score. Safety and tolerability of miltefosine were also assessed. RESULTS: After 4 weeks of treatment, Urticaria Activity Score (UAS7) levels were substantially more reduced in miltefosine-treated patients (-6.3 vs. -3.5 in placebo-treated patients; P = 0.05). Also, the number of weals, but not the intensity of pruritus, was significantly reduced in miltefosine-treated patients vs. placebo-treated patients (P = 0.02). In general, adverse events were frequent in both groups (miltefosine: 88%, placebo: 65% of patients) but mostly mild to moderate in severity. We did not observe any serious adverse events. CONCLUSIONS: The results of this study indicate that miltefosine is an effective and safe treatment option for CSU patients who do not respond to standard-dosed antihistamines.