Publications by authors named "Randolf Brehler"

49 Publications

COVID-19 vaccination of patients with allergies and type-2 inflammation with concurrent antibody therapy (biologicals) - A Position Paper of the German Society of Allergology and Clinical Immunology (DGAKI) and the German Society for Applied Allergology (AeDA).

Allergol Select 2021 1;5:140-147. Epub 2021 Apr 1.

Allergology and Immunology, Department of Dermatotology, Venereology and Allergology, Charité Universitätsmedizin Berlin, Germany.

Background: After the beginning and during the worldwide pandemic caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), patients with allergic and atopic diseases have felt and still feel insecure. Currently, four vaccines against SARS-CoV-2 have been approved by the Paul Ehrlich Institute in Germany, and vaccination campaigns have been started nationwide. In this respect, it is of utmost importance to give recommendations on possible immunological interactions and potential risks of immunomodulatory substances (monoclonal antibodies, biologicals) during concurrent vaccination with the approved vaccines.

Materials And Methods: This position paper provides specific recommendations on the use of immunomodulatory drugs in the context of concurrent SARS-CoV-2 vaccinations based on current literature.

Results: The recommendations are covering the following conditions in which biologicals are indicated and approved: 1) chronic inflammatory skin diseases (atopic dermatitis, chronic spontaneous urticaria), 2) bronchial asthma, and 3) chronic rhinosinusitis with nasal polyps (CRSwNP). Patients with atopic dermatitis or chronic spontaneous urticaria are not at increased risk for allergic reactions after COVID-19 vaccination. Nevertheless, vaccination may result in transient eczema exacerbation due to general immune stimulation. Vaccination in patients receiving systemic therapy with biologicals can be performed. Patients with severe asthma and concomitant treatment with biologicals also do not have an increased risk of allergic reaction following COVID-19 vaccination which is recommended in these patients. Patients with CRSwNP are also not known to be at increased risk for allergic vaccine reactions, and continuation or initiation of a treatment with biologicals is also recommended with concurrent COVID-19 vaccination. In general, COVID-19 vaccination should be given within the interval between two applications of the respective biological, that is, with a time-lag of at least 1 week after the previous or at least 1 week before the next biological treatment planned.

Conclusion: Biologicals for the treatment of atopic dermatitis, chronic spontaneous urticaria, bronchial asthma, and CRSwNP should be continued during the current COVID-19 vaccination campaigns. However, the intervals of biological treatment may need to be slightly adjusted (DGAKI/AeDA recommendations as of March 22, 2021).
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http://dx.doi.org/10.5414/ALX02241EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028287PMC
April 2021

Complex -Glycans Are Important for Normal Fruit Ripening and Seed Development in Tomato.

Front Plant Sci 2021 9;12:635962. Epub 2021 Mar 9.

Institute of Plant Biology and Biotechnology, University of Münster, Münster, Germany.

Complex -glycan modification of secretory glycoproteins in plants is still not well understood. Essential in animals, where a lack of complex -glycans is embryo-lethal, their presence in plants seemed less relevant for a long time mostly because mutants lacking -acetyl-glucosaminyltransferase I (GNTI, the enzyme initiating complex -glycan maturation in the Golgi apparatus) are viable and showed only minor impairments regarding stress tolerance or development. A different picture emerged when a rice () T-DNA mutant was found to be unable to reach the reproductive stage. Here, we report on tomato () lines that showed severe impairments upon two RNA interference (RNAi) approaches. Originally created to shed light on the role of α1,3-fucose and β1,2-xylose residues in food allergy, plants with strongly reduced GNTI activity developed necrotic fruit-attached stalks and early fruit drop combined with patchy incomplete ripening. Correspondingly, semiquantitative RT-PCR of the abscission zone (az) revealed an increase of abscission markers. Also, -RNA interference (RNAi) plants were more susceptible to sporadic infection. To obtain vital tomatoes with comparable low allergenic potential, Golgi α-mannosidase II (MANII) was chosen as the second target. The resulting phenotypes were oppositional: MANII-reduced plants carried normal-looking fruits that remained attached for extended time without signs of necrosis. Fruits contained no or only few, but enlarged, seeds. Furthermore, leaves developed rolled-up rims simultaneously during the reproductive stage. Trials to cross MANII-reduced plants failed, while GNTI-reduced plants could be (back-)crossed, retaining their characteristic phenotype. This phenotype could not be overcome by ethephon or indole-3-acetic acid (IAA) application, but the latter was able to mimic patchy fruit ripening in wild-type. Phytohormones measured in leaves and 1-aminocyclopropane-1-carboxylic acid (ACC) contents in fruits showed no significant differences. Together, the findings hint at altered liberation/perception of protein-bound -glycans, known to trigger auxin-like effects. Concomitantly, semiquantitative RT-PCR analysis revealed differences in auxin-responsive genes, indicating the importance of complex -glycan modification for hormone signaling/crosstalk. Another possible role of altered glycoprotein life span seems subordinate, as concluded from transient expression of Arabidopsis KORRIGAN KOR1-GFP fusion proteins in RNAi plants of . In summary, our analyses stress the importance of complex glycan maturation for normal plant responses, especially in fruit-bearing crops like tomato.
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http://dx.doi.org/10.3389/fpls.2021.635962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985349PMC
March 2021

Severe allergic reactions after COVID-19 vaccination with the Pfizer/BioNTech vaccine in Great Britain and USA: Position statement of the German Allergy Societies: Medical Association of German Allergologists (AeDA), German Society for Allergology and Clinical Immunology (DGAKI) and Society for Pediatric Allergology and Environmental Medicine (GPA).

Allergo J Int 2021 24;30(2):51-55. Epub 2021 Feb 24.

Allergologie und Immunologie, Klinik für Dermatologie, Venerologie und Allergologie, Charité - Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany.

Two employees of the National Health Service (NHS) in England developed severe allergic reactions following administration of BNT162b2 vaccine against COVID-19 (coronavirus disease 2019). The British SmPC for the BNT162b2 vaccine already includes reference to a contraindication for use in individuals who have had an allergic reaction to the vaccine or any of its components. As a precautionary measure, the Medicines and Healthcare products Regulatory Agency (MHRA) has issued interim guidance to the NHS not to vaccinate in principle in "patients with severe allergies". Allergic reactions to vaccines are very rare, but vaccine components are known to cause allergic reactions. BNT162b2 is a vaccine based on an mRNA embedded in lipid nanoparticles and blended with other substances to enable its transport into the cells. In the pivotal phase III clinical trial, the BNT162b2 vaccine was generally well tolerated, but this large clinical trial, used to support vaccine approval by the MHRA and US Food and Drug Administration, excluded individuals with a "history of a severe adverse reaction related to the vaccine and/or a severe allergic reaction (e.g., anaphylaxis) to a component of the study medication". Vaccines are recognized as one of the most effective public health interventions. This repeated administration of a foreign protein (antigen) necessitates a careful allergological history before each application and diagnostic clarification and a risk-benefit assessment before each injection. Severe allergic reactions to vaccines are rare but can be life-threatening, and it is prudent to raise awareness of this hazard among vaccination teams and to take adequate precautions while more experience is gained with this new vaccine.
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http://dx.doi.org/10.1007/s40629-020-00160-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903024PMC
February 2021

Healthcare provision for insect venom allergy patients during the COVID-19 pandemic.

Allergo J Int 2020 8;29(8):257-261. Epub 2020 Dec 8.

Department and Outpatient Clinic for Dermatology and Allergology, University Hospital Munich, Munich, Germany.

The population prevalence of insect venom allergy ranges between 3-5%, and it can lead to potentially life-threatening allergic reactions. Patients who have experienced a systemic allergic reaction following an insect sting should be referred to an allergy specialist for diagnosis and treatment. Due to the widespread reduction in outpatient and inpatient care capacities in recent months as a result of the COVID-19 pandemic, the various allergy specialized centers in Germany, Austria, and Switzerland have taken different measures to ensure that patients with insect venom allergy will continue to receive optimal allergy care. A recent data analysis from the various centers revealed that there has been a major reduction in newly initiated insect venom immunotherapy (a 48.5% decline from March-June 2019 compared to March-June 2020: data from various centers in Germany, Austria, and Switzerland). The present article proposes defined organizational measures (e.g., telephone and video appointments, rearranging waiting areas and implementing hygiene measures and social distancing rules at stable patient numbers) and medical measures (collaboration with practice-based physicians with regard to primary diagnostics, rapid COVID-19 testing, continuing already-initiated insect venom immunotherapy in the outpatient setting by making use of the maximal permitted injection intervals, prompt initiation of insect venom immunotherapy during the summer season, and, where necessary, using outpatient regimens particularly out of season) for the care of insect venom allergy patients during the COVID-19 pandemic.
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http://dx.doi.org/10.1007/s40629-020-00157-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7722411PMC
December 2020

Hybridkongress gelungen - online wie offline gut besucht.

Allergo J 2020 9;29(7):52-53. Epub 2020 Nov 9.

Wilhelm-Univ. Münster, Abtlg. Dermatologie, Von-Esmarch-Str. 58, 48149 Münster, Germany.

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http://dx.doi.org/10.1007/s15007-020-2619-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605128PMC
November 2020

Allergologie zwischen Grenzen und Möglichkeiten.

Allergo J 2020 21;29(6):36. Epub 2020 Sep 21.

Klinik f. Dermatologie, Venerologie u. Allergologie, Robert-Koch-Str. 40, 37075 Göttingen, Germany.

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http://dx.doi.org/10.1007/s15007-020-2596-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483486PMC
September 2020

Use of biologicals in allergic and type-2 inflammatory diseases during the current COVID-19 pandemic: Position paper of Ärzteverband Deutscher Allergologen (AeDA), Deutsche Gesellschaft für Allergologie und Klinische Immunologie (DGAKI), Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA), Österreichische Gesellschaft für Allergologie und Immunologie (ÖGAI), Luxemburgische Gesellschaft für Allergologie und Immunologie (LGAI), Österreichische Gesellschaft für Pneumologie (ÖGP) in co-operation with the German, Austrian, and Swiss ARIA groups, and the European Academy of Allergy and Clinical Immunology (EAACI).

Authors:
Ludger Klimek Oliver Pfaar Margitta Worm Thomas Eiwegger Jan Hagemann Markus Ollert Eva Untersmayr Karin Hoffmann-Sommergruber Alessandra Vultaggio Ioana Agache Sevim Bavbek Apostolos Bossios Ingrid Casper Susan Chan Alexia Chatzipetrou Christian Vogelberg Davide Firinu Paula Kauppi Antonios Kolios Akash Kothari Andrea Matucci Oscar Palomares Zsolt Szépfalusi Wolfgang Pohl Wolfram Hötzenecker Alexander R Rosenkranz Karl-Christian Bergmann Thomas Bieber Roland Buhl Jeroen Buters Ulf Darsow Thomas Keil Jörg Kleine-Tebbe Susanne Lau Marcus Maurer Hans Merk Ralph Mösges Joachim Saloga Petra Staubach Uta Jappe Klaus F Rabe Uta Rabe Claus Vogelmeier Tilo Biedermann Kirsten Jung Wolfgang Schlenter Johannes Ring Adam Chaker Wolfgang Wehrmann Sven Becker Laura Freudelsperger Norbert Mülleneisen Katja Nemat Wolfgang Czech Holger Wrede Randolf Brehler Thomas Fuchs Peter-Valentin Tomazic Werner Aberer Antje-Henriette Fink-Wagner Fritz Horak Stefan Wöhrl Verena Niederberger-Leppin Isabella Pali-Schöll Wolfgang Pohl Regina Roller-Wirnsberger Otto Spranger Rudolf Valenta Mübecell Akdis Paolo M Matricardi François Spertini Nicolai Khaltaev Jean-Pierre Michel Larent Nicod Peter Schmid-Grendelmeier Marco Idzko Eckard Hamelmann Thilo Jakob Thomas Werfel Martin Wagenmann Christian Taube Erika Jensen-Jarolim Stephanie Korn Francois Hentges Jürgen Schwarze Liam O Mahony Edward F Knol Stefano Del Giacco Tomás Chivato Pérez Jean Bousquet Anna Bedbrook Torsten Zuberbier Cezmi Akdis Marek Jutel

Allergol Select 2020 7;4:53-68. Epub 2020 Sep 7.

European Academy of Allergy and Clinical Immunology (EAACI).

Background: Since the beginning of the COVID-19 pandemic, the treatment of patients with allergic and atopy-associated diseases has faced major challenges. Recommendations for "social distancing" and the fear of patients becoming infected during a visit to a medical facility have led to a drastic decrease in personal doctor-patient contacts. This affects both acute care and treatment of the chronically ill. The immune response after SARS-CoV-2 infection is so far only insufficiently understood and could be altered in a favorable or unfavorable way by therapy with monoclonal antibodies. There is currently no evidence for an increased risk of a severe COVID-19 course in allergic patients. Many patients are under ongoing therapy with biologicals that inhibit type 2 immune responses via various mechanisms. There is uncertainty about possible immunological interactions and potential risks of these biologicals in the case of an infection with SARS-CoV-2.

Materials And Methods: A selective literature search was carried out in PubMed, Livivo, and the internet to cover the past 10 years (May 2010 - April 2020). Additionally, the current German-language publications were analyzed. Based on these data, the present position paper provides recommendations for the biological treatment of patients with allergic and atopy-associated diseases during the COVID-19 pandemic.

Results: In order to maintain in-office consultation services, a safe treatment environment must be created that is adapted to the pandemic situation. To date, there is a lack of reliable study data on the care for patients with complex respiratory, atopic, and allergic diseases in times of an imminent infection risk from SARS-CoV-2. Type-2-dominant immune reactions, as they are frequently seen in allergic patients, could influence various phases of COVID-19, e.g., by slowing down the immune reactions. Theoretically, this could have an unfavorable effect in the early phase of a SARS-Cov-2 infection, but also a positive effect during a cytokine storm in the later phase of severe courses. However, since there is currently no evidence for this, all data from patients treated with a biological directed against type 2 immune reactions who develop COVID-19 should be collected in registries, and their disease courses documented in order to be able to provide experience-based instructions in the future.

Conclusion: The use of biologicals for the treatment of bronchial asthma, atopic dermatitis, chronic rhinosinusitis with nasal polyps, and spontaneous urticaria should be continued as usual in patients without suspected infection or proven SARS-CoV-2 infection. If available, it is recommended to prefer a formulation for self-application and to offer telemedical monitoring. Treatment should aim at the best possible control of difficult-to-control allergic and atopic diseases using adequate rescue and add-on therapy and should avoid the need for systemic glucocorticosteroids. If SARS-CoV-2 infection is proven or reasonably suspected, the therapy should be determined by weighing the benefits and risks individually for the patient in question, and the patient should be involved in the decision-making. It should be kept in mind that the potential effects of biologicals on the immune response in COVID-19 are currently not known. Telemedical offers are particularly desirable for the acute consultation needs of suitable patients.
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http://dx.doi.org/10.5414/ALX02166EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480069PMC
September 2020

Chronisch rezidivierendes Angioödem.

Authors:
Randolf Brehler

Pneumo News 2020 14;12(4):34-37. Epub 2020 Jul 14.

Wilhelm-Univ. Münster, Abtlg. Dermatologie, Von-Esmarch-Str. 58, 48149 Münster, Deutschland.

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http://dx.doi.org/10.1007/s15033-020-1859-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7332843PMC
July 2020

Allergen immunotherapy in the current COVID-19 pandemic: A position paper of AeDA, ARIA, EAACI, DGAKI and GPA: Position paper of the German ARIA Group in cooperation with the Austrian ARIA Group, the Swiss ARIA Group, German Society for Applied Allergology (AEDA), German Society for Allergology and Clinical Immunology (DGAKI), Society for Pediatric Allergology (GPA) in cooperation with AG Clinical Immunology, Allergology and Environmental Medicine of the DGHNO-KHC and the European Academy of Allergy and Clinical Immunology (EAACI).

Allergol Select 2020 28;4:44-52. Epub 2020 May 28.

German ARIA Group.

No abstract available.
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http://dx.doi.org/10.5414/ALX02147EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304289PMC
May 2020

Guideline on diagnostic procedures for suspected hypersensitivity to beta-lactam antibiotics: Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in collaboration with the German Society of Allergology (AeDA), German Society for Pediatric Allergology and Environmental Medicine (GPA), the German Contact Dermatitis Research Group (DKG), the Austrian Society for Allergology and Immunology (ÖGAI), and the Paul-Ehrlich Society for Chemotherapy (PEG).

Allergol Select 2020 28;4:11-43. Epub 2020 May 28.

Department of Dermatology and Allergology am Biederstein, School of Medicine, Technical University of Munich, Munich, Germany.

This guideline on diagnostic procedures for suspected beta-lactam antibiotic (BLA) hypersensitivity was written by the German and Austrian professional associations for allergology, and the Paul-Ehrlich Society for Chemotherapy in a consensus procedure according to the criteria of the German Association of Scientific Medical Societies. BLA such as penicillins and cephalosporins represent the drug group that most frequently triggers drug allergies. However, the frequency of reports of suspected allergy in patient histories clearly exceeds the number of confirmed cases. The large number of suspected BLA allergies has a significant impact on, e.g., the quality of treatment received by the individual patient and the costs to society as a whole. Allergies to BLA are based on different immunological mechanisms and often manifest as maculopapular exanthema, as well as anaphylaxis; and there are also a number of less frequent special clinical manifestations of drug allergic reactions. All BLA have a beta-lactam ring. BLA are categorized into different classes: penicillins, cephalosporins, carbapenems, monobactams, and beta-lactamase inhibitors with different chemical structures. Knowledge of possible cross-reactivity is of considerable clinical significance. Whereas allergy to the common beta-lactam ring occurs in only a small percentage of all BLA allergic patients, cross-reactivity due to side chain similarities, such as aminopenicillins and aminocephalosporins, and even methoxyimino cephalosporins, are more common. However, the overall picture is complex and its elucidation may require further research. Diagnostic procedures used in BLA allergy are usually made up of four components: patient history, laboratory diagnostics, skin testing (which is particularly important), and drug provocation testing. The diagnostic approach - even in cases where the need to administer a BLA is acute - is guided by patient history and risk - benefit ratio in the individual case. Here again, further studies are required to extend the present state of knowledge. Performing allergy testing for suspected BLA hypersensitivity is urgently recommended not only in the interests of providing the patient with good medical care, but also due to the immense impact of putative BLA allergies on society as a whole.
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http://dx.doi.org/10.5414/ALX02104EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7304290PMC
May 2020

Anwendung von Biologika bei allergischen und Typ-2-entzündlichen Erkrankungen in der aktuellen Covid-19-Pandemie: Positionspapier des Ärzteverbands Deutscher Allergologen (AeDA)A, der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI)B, der Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA)C, der Österreichischen Gesellschaft für Allergologie und Immunologie (ÖGAI)D, der Luxemburgischen Gesellschaft für Allergologie und Immunologie (LGAI)E, der Österreichischen Gesellschaft für Pneumologie (ÖGP)F in Kooperation mit der deutschen, österreichischen, und schweizerischen ARIA-GruppeG und der Europäischen Akademie für Allergologie und Klinische Immunologie (EAACI)H.

Allergo J 2020 24;29(4):14-27. Epub 2020 Jun 24.

Zentrum für Rhinologie & Allergologie, An den Quellen 10, 65183 Wiesbaden, Germany.

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http://dx.doi.org/10.1007/s15007-020-2553-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289636PMC
June 2020

COVID-19 pandemic: Practical considerations on the organization of an allergy clinic-An EAACI/ARIA Position Paper.

Allergy 2021 03;76(3):648-676

Transylvania University, Brasov, Romania.

Background: The coronavirus disease 2019 (COVID-19) has evolved into a pandemic infectious disease transmitted by the severe acute respiratory syndrome coronavirus (SARS-CoV-2). Allergists and other healthcare providers (HCPs) in the field of allergies and associated airway diseases are on the front line, taking care of patients potentially infected with SARS-CoV-2. Hence, strategies and practices to minimize risks of infection for both HCPs and treated patients have to be developed and followed by allergy clinics.

Method: The scientific information on COVID-19 was analysed by a literature search in MEDLINE, PubMed, the National and International Guidelines from the European Academy of Allergy and Clinical Immunology (EAACI), the Cochrane Library, and the internet.

Results: Based on the diagnostic and treatment standards developed by EAACI, on international information regarding COVID-19, on guidelines of the World Health Organization (WHO) and other international organizations, and on previous experience, a panel of experts including clinicians, psychologists, IT experts, and basic scientists along with EAACI and the "Allergic Rhinitis and its Impact on Asthma (ARIA)" initiative have developed recommendations for the optimal management of allergy clinics during the current COVID-19 pandemic. These recommendations are grouped into nine sections on different relevant aspects for the care of patients with allergies.

Conclusions: This international Position Paper provides recommendations on operational plans and procedures to maintain high standards in the daily clinical care of allergic patients while ensuring the necessary safety measures in the current COVID-19 pandemic.
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http://dx.doi.org/10.1111/all.14453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7323448PMC
March 2021

Ligelizumab for Chronic Spontaneous Urticaria.

N Engl J Med 2019 10;381(14):1321-1332

From the Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin (M. Maurer, M. Metz), the Department of Dermatology, University Allergy Center, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden (A. Bauer), the Department of Dermatology, University Hospital Münster, Münster (R.B.), the Department of Dermatology, University Medical Center Mainz, Mainz (P.S.), and the Department of Dermatology and Allergy, Comprehensive Allergy Center, Hannover Medical School, Hannover (B.W.) - all in Germany; the Dermatology Department, Hospital del Mar-Institut Hospital del Mar d'Investigacions Mèdiques, Universitat Autònoma Barcelona, Barcelona (A.M.G.-A.); the Division of Allergy and Clinical Immunology, St. Michael's Hospital and University of Toronto, Toronto (G.S.), Service d'Allergie, Centre Hospitalier Université Laval-Centre Hospitalier Universitaire de Québec, Quebec, QC (J.H.), and the Department of Medicine, University of Ottawa, Ottawa (K.K.) - all in Canada; Baker Allergy Asthma and Dermatology Clinic, Portland, OR (D.R.B.); University of Cincinnati College of Medicine, Department of Internal Medicine, Division of Immunology, Rheumatology, and Allergy and Bernstein Clinical Research Center, Cincinnati (J.A.B.); the Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine (C.-Y.C.), and the Department of Dermatology, Chang Gung Memorial Hospital (W.-H.C.), Taipei, Taiwan; the National Research Center-Institute of Immunology Federal Medical-Biological Agency of Russia, Moscow (I.D.), and the Department of Clinical Immunology and Allergology, Smolensk State Medical University, Smolensk (R.M.) - both in Russia; St. John's Institute of Dermatology, Guy's and St. Thomas' Hospitals NHS Foundation Trust, London (C.G.), and the National Institute for Health Research-Leeds Biomedical Research Centre and Leeds Institute of Rheumatic and Musculoskeletal Medicine, and the Department of Clinical Immunology and Allergy, St. James's University Hospital, Leeds (S.S.) - all in the United Kingdom; the School of Medicine, Western Sydney University, and the Immunology and Allergy Unit, Campbelltown Hospital, Campbelltown, NSW (C.K.), and Sinclair Dermatology and the Epworth Hospital, Melbourne, VIC (R.S.) - all in Australia; the Second Department of Dermatology and Venereology, Attikon University Hospital, Athens (M. Makris); Little Rock Allergy and Asthma Clinic, Little Rock, AR (K.S.); Novartis Pharma, Basel, Switzerland (J.L., T.S., R.J.); Novartis Pharmaceuticals, East Hanover, NJ (A. Barve, K.K.); and Shanghai Novartis Trading, Shanghai, China (E.H.).

Background: In the majority of patients with chronic spontaneous urticaria, most currently available therapies do not result in complete symptom control. Ligelizumab is a next-generation high-affinity humanized monoclonal anti-IgE antibody. Data are limited regarding the dose-response relationship of ligelizumab and the efficacy and safety of ligelizumab as compared with omalizumab and placebo in patients who have moderate-to-severe chronic spontaneous urticaria that is inadequately controlled with H-antihistamines at approved or increased doses, alone or in combination with H-antihistamines or leukotriene-receptor antagonists.

Methods: In a phase 2b dose-finding trial, we randomly assigned patients to receive ligelizumab at a dose of 24 mg, 72 mg, or 240 mg, omalizumab at a dose of 300 mg, or placebo, administered subcutaneously every 4 weeks for a period of 20 weeks, or a single 120-mg dose of ligelizumab. Disease symptoms of hives, itch, and angioedema were monitored by means of weekly activity scores. The main objective was to determine a dose-response relationship for the complete control of hives (indicated by a weekly hives-severity score of 0, on a scale from 0 to 21, with higher scores indicating greater severity); the primary end point of this response was assessed at week 12. Complete symptom control was indicated by a weekly urticaria activity score of 0 (on a scale from 0 to 42, with higher scores indicating greater severity). Safety was analyzed throughout the trial.

Results: A total of 382 patients underwent randomization. At week 12, a total of 30%, 51%, and 42% of the patients treated with 24 mg, 72 mg, and 240 mg, respectively, of ligelizumab had complete control of hives, as compared with 26% of the patients in the omalizumab group and no patients in the placebo group. A dose-response relationship was established. At week 12, a total of 30%, 44%, and 40% of the patients treated with 24 mg, 72 mg, and 240 mg, respectively, of ligelizumab had complete control of symptoms, as compared with 26% of the patients in the omalizumab group and no patients in the placebo group. In this small and short trial, no safety concerns regarding ligelizumab or omalizumab emerged.

Conclusions: A higher percentage of patients had complete control of symptoms of chronic spontaneous urticaria with ligelizumab therapy of 72 mg or 240 mg than with omalizumab or placebo. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT02477332.).
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http://dx.doi.org/10.1056/NEJMoa1900408DOI Listing
October 2019

Omalizumab normalizes the gene expression signature of lesional skin in patients with chronic spontaneous urticaria: A randomized, double-blind, placebo-controlled study.

Allergy 2019 01 15;74(1):141-151. Epub 2018 Oct 15.

Department of Dermatology and Allergy, Charité - Universitätsmedizin, Berlin, Germany.

Background: Omalizumab, a humanized recombinant monoclonal anti-IgE antibody, proved to be effective in patients with chronic spontaneous urticaria (CSU), including severe and treatment-refractory CSU. Here, we report omalizumab's effect on gene expression in skin biopsies from CSU patients enrolled in a double-blind, placebo-controlled study.

Methods: Chronic spontaneous urticaria patients (18-75 years) were randomized to either 300 mg omalizumab (n = 20) or placebo (n = 10) administered s.c. every 4 weeks for 12 weeks (NCT01599637). Lesional and nonlesional skin biopsies were collected from the same area of consenting patients and assessed at baseline and on Day 85 compared with skin biopsies from the same area of 10 untreated healthy volunteers (HVs). Gene expression data were generated using Affymetrix HG-U133Plus2.0 microarrays. Statistical analyses were performed using R packages.

Results: At baseline, 63 transcripts were differentially expressed between lesional and nonlesional skin. Two-thirds of these lesional signatures were also differentially expressed between lesional and HV skin. Upon treatment with omalizumab, >75% of lesional signatures changed to reflect nonlesional skin expression levels (different vs placebo, P < 0.01). Transcripts upregulated in lesional skin (vs nonlesional and/or HV skin) suggested increased mast cell/leukocyte infiltration (FCER1G, C3AR1, CD93, S100A8, and S100A9), increased oxidative stress, vascularization (CYR61), and skin repair events (KRT6A, KRT16). Lesional signatures were not modulated by treatment in nonresponders (defined based on UAS7 longitudinal changes ≥16).

Conclusion: Omalizumab, in treatment responders, reverted transcriptional signatures associated with CSU lesion phenotype to reflect nonlesional/HV expression levels; this is consistent with observed omalizumab-mediated clinical improvement observed in patients with CSU.
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http://dx.doi.org/10.1111/all.13547DOI Listing
January 2019

Aluminium (Al) speciation in serum and urine after subcutaneous venom immunotherapy with Al as adjuvant.

J Trace Elem Med Biol 2018 Sep 21;49:178-183. Epub 2018 Feb 21.

Universitätsklinikum Münster, Klinik für Hautkrankheiten, Allergologie, Berufsdermatologie und Umweltmedizin, Von-Esmarch-Straße 58, 48149 Münster, Germany.

Background: Aluminium is associated with disorders and is the commonly used vaccine adjuvant. Understanding the mechanisms of how Al is transported, metabolized or of its toxicity depends on the knowledge of Al-interactions with bioligands, i.e. Al-species. Al-speciation in serum is difficult because of low concentration and the risk of exogenous Al contamination. Furthermore, Al-measurements may be hampered according to various interferences. This study aims for developing quality controlled protocols for reliable Al- and Al-species determination and for investigating probable differences in Al (-speciation) after Al-containing subcutaneous immunotherapy (SIT).

Methods: Sample donors were recruited either for the control group ("class-0", they never had been treated with SIT containing an Al-depot extract) or for the SIT-group ("class-1", they previously had been treated with SIT for insect venom allergy with an Al-depot extract). Blood was drawn for medical reasons and serum prepared. Additionally, some sample donors collected 24-h-urine. They had been informed (and they consented) about the scientific use of their samples. The study was approved by the ethic committee of the "Medical Association Westphalia-Lippe" and of the University of Münster, evaluating the study positively (No. 2013-667-f-S). We applied quality controlled sample preparation and interference-free Al detection by ICP sectorfield-mass spectrometry. Al-species were analysed using size-exclusion-chromatography-ICP-qMS.

Findings: Al-concentrations or speciation in urine samples showed no differences between class-0 and class-1. Al-citrate was the main uric Al-species. In serum elevated Al-concentrations were found for both classes, with class-1 samples being significantly higher than class-0 (p = 0.041), but class-0 samples being approximately 10-fold too high compared to reference values from non-exposed persons. We identified gel-monovettes as contamination source. In contamination-free samples from HNO-prewashed gel-free monovettes (n = 27) there was no difference in the serum Al concentration between the two patient groups (p = 0.669) INTERPRETATION: Thorough cleaning of sample preparation ware and use of gel-free monovettes is decisive for an accurate Al analysis in serum. Without these steps, wrong analysis and wrong conclusions are likely. We conclude that gel-monovettes are unsuitable for blood sampling with subsequent Al-analysis. Whether Al in serum is elevated after SIT treatment containing an Al-depot extract, or not, remains inconclusive as the non-contaminated sample size was small.
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http://dx.doi.org/10.1016/j.jtemb.2018.02.014DOI Listing
September 2018

A Case of Severe Anaphylaxis to Polyhexanide: Cross-Reactivity between Biguanide Antiseptics.

Int Arch Allergy Immunol 2017 29;173(4):233-236. Epub 2017 Aug 29.

Department of Dermatology, University Hospital Münster, Münster, Germany.

We present the case of a 77-year-old female patient who suffered from severe anaphylaxis during wound care. Allergologic evaluation yielded specific IgE antibodies to chlorhexidine, but anaphylaxis to chlorhexidine was not congruent with the patient history and dermal provocation tests. However, skin prick tests provided evidence for a sensitization to polyhexanide that was further supported by the detection of specific IgE antibodies to polyhexanide, the results of basophil activation tests and IgE inhibition analysis. We presume cross-reactive IgE antibodies binding to both biguanide antiseptics and identified polyhexanide as the likely cause of the anaphylactic reaction. We recognize polyhexanide as an emerging allergen that has to be considered as a cause of anaphylaxis.
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http://dx.doi.org/10.1159/000478700DOI Listing
October 2017

Omalizumab treatment in patients with chronic inducible urticaria: A systematic review of published evidence.

J Allergy Clin Immunol 2018 02 24;141(2):638-649. Epub 2017 Jul 24.

Department of Dermatology and Allergy, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Background: Omalizumab, a recombinant anti-IgE antibody, effectively treats chronic spontaneous urticaria. Evidence is lacking in patients with chronic inducible urticarias (CIndUs), which are frequently H-antihistamine resistant.

Objective: From the current published literature, we aimed to determine the strength of evidence for omalizumab efficacy and safety in the treatment of CIndUs.

Methods: We performed a PubMed search to identify evidence on omalizumab use in the following 9 CIndU subtypes: symptomatic dermographism, cold urticaria, delayed-pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticaria, and aquagenic urticaria.

Results: Forty-three trials, case studies, case reports, and analyses were identified. Our review indicates that omalizumab has substantial benefits in patients with various CIndUs. The evidence is strongest for symptomatic dermographism, cold urticaria, and solar urticaria. Little/no evidence was available on vibratory angioedema and aquagenic and contact urticaria. Our review supports rapid onset of action demonstrated through early symptom control in most cases, sometimes within 24 hours. Many patients gained complete/partial symptom relief and substantially improved quality of life. Adverse events were generally low, with omalizumab being well tolerated by most patients, including children.

Conclusions: A strong body of evidence supports the use of omalizumab in the treatment of patients with therapy-refractory CIndU. More data from randomized controlled studies are warranted.
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http://dx.doi.org/10.1016/j.jaci.2017.06.032DOI Listing
February 2018

Clinical efficacy of omalizumab in chronic spontaneous urticaria is associated with a reduction of FcεRI-positive cells in the skin.

Theranostics 2017 6;7(5):1266-1276. Epub 2017 Mar 6.

Department of Dermatology and Allergy, Charité - Universitätsmedizin, Berlin, Germany.

Treatment with omalizumab, a humanized recombinant monoclonal anti-IgE antibody, results in clinical efficacy in patients with Chronic Spontaneous Urticaria (CSU). The mechanism of action of omalizumab in CSU has not been elucidated in detail. To determine the effects of omalizumab on levels of high affinity IgE receptor-positive (FcεRI) and IgE-positive (IgE) dermal cells and blood basophils. Treatment efficacy and safety were also assessed. In a double-blind study, CSU patients aged 18‑75 years were randomized to receive 300 mg omalizumab (n=20) or placebo (n=10) subcutaneously every 4 weeks for 12 weeks. Changes in disease activity were assessed by use of the weekly Urticaria Activity Score (UAS7). Circulating IgE levels, basophil numbers and levels of expression of FcεRI and IgE cells in the skin and in blood basophils were determined. Patients receiving omalizumab showed a significantly greater decrease in UAS7 compared with patients receiving placebo. At Week 12 the mean difference in UAS7 between treatment groups was -14.82 (p=0.0027), consistent with previous studies. Total IgE levels in serum were increased after omalizumab treatment and remained elevated up to Week 12. Free IgE levels decreased after omalizumab treatment. Mean levels of FcεRI skin cells in patients treated with omalizumab 300 mg were decreased at Week 12 compared with baseline in the dermis of both non-lesional and lesional skin, reaching levels comparable with those seen in healthy volunteers (HVs). There were no statistically significant changes in mean FcɛRI cell levels in the placebo group. Similar results were seen for changes in IgE cells, although the changes were not statistically significant. The level of peripheral blood basophils increased immediately after treatment start and returned to Baseline values after the follow-up period. The levels of FcεRI and IgE expression on peripheral blood basophils were rapidly reduced by omalizumab treatment up to Week 12. Treatment with omalizumab resulted in rapid clinical benefits in patients with CSU. Treatment with omalizumab was associated with reduction in FcɛRI and IgE basophils and intradermal cells.
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http://dx.doi.org/10.7150/thno.18304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399592PMC
January 2018

Blindness, tetraspasticity, and other signs of irreversible brain damage in hereditary angioedema.

Ann Allergy Asthma Immunol 2017 Apr 6;118(4):520-521. Epub 2017 Mar 6.

Department of Medical Psychology and Medical Sociology, Johannes Gutenberg University, Mainz, Germany.

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http://dx.doi.org/10.1016/j.anai.2017.01.027DOI Listing
April 2017

Evidence vs. efficacy in allergen-specific immunotherapy: Considerations using the example of tradable products in Germany.

Allergo J Int 2016;25:38-43. Epub 2016 Mar 23.

Ruhr Allergy Center, Ruhr University Bochum, Germany ; Bethel Pediatric Center, Bielefeld, Germany.

The recently published S2k-guideline on (allergen-) specific immunotherapy (AIT) provides an excellent overview of the evidence on allergen preparations available for AIT in Germany based on the published efficacy studies. Publications based on the guideline are currently being used by the German associations of statutory health insurance physicians and German health insurance funds to open a discussion on the reimbursement status of allergen preparations. In our view, calling the reimbursement status of perscribable and tradable AIT preparations into question on the basis of an assessment of the current body of evidence in the guideline is to be rigidly opposed. In Germany the Paul Ehrlich Institute (PEI) is the only authority empowered to decide on the marketability of AIT preparations, and decisions on the reimbursement status of AIT products need to be based on cost-benefit analyses and not solely on an evaluation of the evidence. The present article aims to examine the relationship between the evidence, efficacy, tradability, and reimbursability of AIT preparations.
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http://dx.doi.org/10.1007/s40629-016-0096-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4861740PMC
March 2016

Neutrophilic Epitheliotropism is a Histopathological Clue to Neutrophilic Urticarial Dermatosis.

Am J Dermatopathol 2016 Jan;38(1):39-49

*Department of Dermatology, University of Münster, Münster, Germany; †Dermatopathology Laboratory, Dermatologikum, Hamburg, Germany; ‡Department of Dermatology, University of Zürich, Zürich, Switzerland; and §Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany.

Background: Neutrophilic urticarial dermatosis (NUD) comprises a particular autoinflammatory condition within the spectrum of aseptic neutrophilic dermatoses characterized by a distinct urticarial eruption clinically and a neutrophilic dermatosis histopathologically.

Objective: In this study, we reviewed skin biopsies of lesional skin of patients seen in our outpatient clinic for autoimmune dermatoses and in allergy department from 1982 to 2014 that fulfilled these criteria.

Methods: A total of 77 biopsies from 50 patients were analyzed histopathologically. Included were cases of Schnitzler syndrome, Still disease, systemic lupus erythematosus, Sjögren syndrome, cryopyrin-associated periodic syndrome, primary biliary cirrhosis, inflammatory bowel disease, and those that had signs of systemic inflammation not otherwise specified, that is, fever, arthritis, leukocytosis, and elevated erythrocyte sedimentation rate. A control cohort was defined as including a total of 70 biopsies from 50 patients comprising neutrophilic urticaria (pressure-induced and not pressure-induced), conventional urticaria, lupus erythematosus expressing neutrophils, and exanthematous drug reaction of macular type expressing neutrophils.

Results: Skin biopsies of NUD revealed a perivascular and interstitial neutrophilic infiltrate focally extending into the epithelia of epidermis, hair follicles, sebaceous and sweat glands, a feature which we termed neutrophilic epitheliotropism. This neutrophilic epitheliotropism proved to be of high sensitivity (83.1%) and lower specificity (74.3%). The histological findings could be substantiated by immunohistochemical markers for leukocytes (elastase and myeloperoxidase), in particular in cases where neutrophils showed uncharacteristic band-like nuclei.

Conclusions: Neutrophilic epitheliotropism is a new sensitive and specific histopathological clue for NUD, a histopathological reaction pattern within the spectrum of neutrophilic dermatoses that needs to be differentiated from conventional urticaria.
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http://dx.doi.org/10.1097/DAD.0000000000000390DOI Listing
January 2016

Allergy--current insights into prevention and diagnostic workup of immediate-type allergy and treatment of allergic rhinoconjunctivitis.

J Dtsch Dermatol Ges 2015 Aug;13(8):747-62; quiz 763-4

Clinic for Allergology, Occupational Dermatology, and Environmental Medicine, Department of Dermatology, University Medical Center Münster, Münster, Germany.

In recent decades, the incidence of allergic diseases has dramatically increased, by now affecting a large percentage of the population. For a long time, allergen avoidance was considered the most crucial measure in primary allergy prevention. However, studies have increasingly shown that exposure to allergens is an essential prerequisite for the development of immunological tolerance. Diagnostic workup is based on patient history, skin tests, and measurement of specific IgE antibodies. The introduction of component-based diagnostic workup offer an option to differentiate between primary sensitization and cross-reactivity caused by sensitization to panallergens or sensitization to cross-reactive carbohydrate epitopes. Symptomatic treatment only leads to temporary relief of allergic symptoms. By contrast, specific immunotherapy (SIT) may have long-lasting therapeutic effects and potentially even result in a complete cure. The selection of allergens for SIT is guided by the principle of major allergens. It is recommended to use those preparations that have been proven safe and effective in controlled clinical studies. With respect to subcutaneous immunotherapy, a host of tested and approved extracts are available for a wide range of different allergens. Large clinical trials have also confirmed the efficacy of sublingual immunotherapy with grass and also birch pollen extracts, which has led to the official approval of some preparations containing these allergens.
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http://dx.doi.org/10.1111/ddg.12782DOI Listing
August 2015