Publications by authors named "Thomas Werfel"

281 Publications

Eczema herpeticum in atopic dermatitis.

Allergy 2021 Apr 12. Epub 2021 Apr 12.

Department of Dermatology and Allergy, Division of Immunodermatology and Allergy Research, Hannover Medical School, Hannover, Germany.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin disease leading to pruritic skin lesions. A subset of AD patients exhibitsa disseminated severe HSV infection called eczema herpeticum (EH) which can cause life-threatening complications. This review gives an overview of the clinical picture, and characteristics of the patients as well as the diagnosis and therapy of EH. A special focus lies on the pathophysiological hallmarksidentified so farthat predispose for EH. This aspect coversgenetic aberrations, immunological changes and environmental influences displaying a complex multifactorial situation, which is not completely understood.Type 2 skewing of virus-specific T cells in ADEH patients has been implicated in immune profile abnormalities, along withimpaired functions of dendritic cells and natural killer cells. Furthermore, aberrations ininterferon pathway related genes such as IFNG and IFNGR1 have been identified to increase the risk of EH. IL-4, IL-25, and thymic stromal lymphopoietin (TSLP) are overexpressed in EH, whereas antimicrobial peptides like humanβ-defensinsand LL-37 are reduced. Concerning the epidermal barrier, single nucleotide polymorphisms (SNPs) in skin barrier proteins such as filaggrin were identified in ADEH patients. A dysbalance of theskin microbiomealso contributes to EH due to an increase of Staphylococcus aureus, which provides asupporting role to the viral infection via secreted toxins such as a-toxin. The risk of EH is reduced in AD patients treated with dupilumab. Further research is needed to identify and specifically target risk factors for EH in AD patients.
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http://dx.doi.org/10.1111/all.14853DOI Listing
April 2021

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

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

Physiology and pathology of eosinophils: Recent developments: Summary of the Focus Workshop Organized by DGAKI.

Scand J Immunol 2021 Feb 23:e13032. Epub 2021 Feb 23.

Deptment of Dermatology and Allergology Biederstein, Technical University Munich (TUM), Munich, Germany.

Over the last century, eosinophils have been regarded ambiguously either as 'friends' or 'foes'. Recent developments have greatly enhanced our understanding of the role and function of eosinophils in health and disease. Pathogenic eosinophilic inflammation can lead to severe diseases in various organs, such as the gastrointestinal tract, airways, heart and skin. In a 2-day focus workshop of the German Society for Allergology and Clinical Immunology (DGAKI), the state of the art was discussed and practical recommendations for diagnosis and treatment of eosinophilic diseases, with a particular focus on new biologics, such as anti-interleukin 5 and anti-interleukin 5R, were derived.
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http://dx.doi.org/10.1111/sji.13032DOI Listing
February 2021

Leitlinie zu Akuttherapie und Management der Anaphylaxie - Update 2021: S2k-Leitlinie der Deutschen Gesellschaft für Allergologie und klinische Immunologie (DGAKI), des Ärzteverbands Deutscher Allergologen (AeDA), der Gesellschaft für Pädiatrische Allergologie und Umweltmedizin (GPA), der Deutschen Akademie für Allergologie und Umweltmedizin (DAAU), des Berufsverbands der Kinder- und Jugendärzte (BVKJ), der Gesellschaft für Neonatologie und Pädiatrische Intensivmedizin (GNPI), der Deutschen Dermatologischen Gesellschaft (DDG), der Österreichischen Gesellschaft für Allergologie und Immunologie (ÖGAI), der Schweizerischen Gesellschaft für Allergologie und Immunologie (SGAI), der Deutschen Gesellschaft für Anästhesiologie und Intensivmedizin (DGAI), der Deutschen Gesellschaft für Pharmakologie (DGP), der Deutschen Gesellschaft für Pneumologie und Beatmungsmedizin (DGP), der Patientenorganisation Deutscher Allergie- und Asthmabund (DAAB) und der Arbeitsgemeinschaft Anaphylaxie - Training und Edukation (AGATE).

Allergo J 2021 12;30(1):20-49. Epub 2021 Feb 12.

Klinik f. Dermatologie und Allergologie am Biederstein, Biedersteiner Str. 29, 80802 München, Germany.

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http://dx.doi.org/10.1007/s15007-020-4750-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878028PMC
February 2021

EAACI Biologicals Guidelines-dupilumab for children and adults with moderate-to-severe atopic dermatitis.

Allergy 2021 Apr 27;76(4):988-1009. Epub 2020 Dec 27.

Department of Clinical Immunology, University of Wroclaw, Wroclaw, Poland.

Atopic dermatitis imposes a significant burden on patients, families and healthcare systems. Management is difficult, due to disease heterogeneity, co-morbidities, complexity in care pathways and differences between national or regional healthcare systems. Better understanding of the mechanisms has enabled a stratified approach to the management of atopic dermatitis, supporting the use of targeted treatments with biologicals. However, there are still many issues that require further clarification. These include the definition of response, strategies to enhance the responder rate, the duration of treatment and its regimen (in the clinic or home-based), its cost-effectiveness and long-term safety. The EAACI Guidelines on the use of dupilumab in atopic dermatitis follow the GRADE approach in formulating recommendations for each outcome and age group. In addition, future approaches and research priorities are discussed.
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http://dx.doi.org/10.1111/all.14690DOI Listing
April 2021

A negative breakdown test in a fragrance mix I-positive patient does not rule out contact allergy to its fragrance constituents.

Contact Dermatitis 2021 Feb 3. Epub 2021 Feb 3.

Department of Dermatology, Venereology and Allergy, University Medical Center Göttingen, Göttingen, Germany.

Background: In about half of the patients reacting positive to fragrance mix I (FM I), breakdown testing remains negative. This raises the question of whether the reaction to FM I is false-positive, or the breakdown test is false-negative.

Objectives: To identify characteristics and sensitization patterns of patients positive to FM I, but not to its fragrance constituents.

Patients And Methods: Retrospective analysis of data from the Information Network of Departments of Dermatology (IVDK) between 2005 and 2019. Three patient groups were defined according to their reaction pattern: Group I, FM I positive and ≥1 single fragrance positive in the breakdown test (n = 1912); Group II, FM I positive and breakdown test negative (n = 1318); Group III, FM I negative (n = 19 790).

Results: Regarding the pattern of concomitant reactions to other fragrances, Group II had an intermediate position between Group I and Group III. In other respects (age and sex distribution, frequency of sensitization to non-fragrance baseline series allergens), Group II rather resembled Group I.

Conclusions: Not every positive reaction to FM I in patients with negative breakdown tests is false-positive. There may be false-negative reactions to the single fragrance components when patch tested at 1% pet. Raising patch concentrations of some single fragrances is recommended.
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http://dx.doi.org/10.1111/cod.13803DOI Listing
February 2021

Guideline (S2k) on acute therapy and management of anaphylaxis: 2021 update: S2k-Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Medical Association of German Allergologists (AeDA), the Society of Pediatric Allergology and Environmental Medicine (GPA), the German Academy of Allergology and Environmental Medicine (DAAU), the German Professional Association of Pediatricians (BVKJ), the Society for Neonatology and Pediatric Intensive Care (GNPI), the German Society of Dermatology (DDG), the Austrian Society for Allergology and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Anaesthesiology and Intensive Care Medicine (DGAI), the German Society of Pharmacology (DGP), the German Respiratory Society (DGP), the patient organization German Allergy and Asthma Association (DAAB), the German Working Group of Anaphylaxis Training and Education (AGATE).

Allergo J Int 2021 28;30(1):1-25. Epub 2021 Jan 28.

Department Dermatology and Allergology Biederstein, Technical University Munich, Biedersteiner Straße 29, 80802 Munich, Germany.

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http://dx.doi.org/10.1007/s40629-020-00158-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7841027PMC
January 2021

Assessment of the effects of a work-related allergy to seafood on the reduction of earning capacity in the context of BK No. 5101.

Allergol Select 2021 14;5:33-44. Epub 2021 Jan 14.

University of Heidelberg, Heidelberg, Germany.

Fish, crustaceans, and mollusks are among the most potent allergenic foods of animal origin and are thus important triggers of work-related immediate-food allergies. In Germany, work-related seafood allergies are of great importance in the fishing and processing industries as well as in the areas of food preparation, food control, and food sales. There is no causal therapy of seafood allergy, only the strict and lifelong avoidance of allergens remains. The following recommendations serve to assess the impact of a seafood allergy with regard to the work opportunities ended by it for the assessment of the reduction of earning capacity (MdE (German for Minderung der Erwerbsfähigkeit)) in the context of the occupational disease number 5101 of the Annex to the German regulation for occupational diseases. As a special feature of work-related seafood allergy with regard to insurance law aspects, it must be taken into account that there is a potential risk of systemic reaction with subsequent multi-organ involvement. For the estimation of MdE in the general labor market, the impact of a seafood allergy can therefore be assessed, depending on its clinical severity, as generally "mild" to "severe" in justified individual cases.
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http://dx.doi.org/10.5414/AL0DB380EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814778PMC
January 2021

Update "Systemic treatment of atopic dermatitis" of the S2k-guideline on atopic dermatitis.

J Dtsch Dermatol Ges 2021 Jan;19(1):151-168

Fachbereich Pädiatrische Dermatologie und Allergologie, Kinder- und Jugendkrankenhaus Auf der Bult, Hannover.

This guideline is an update from August 2020 the S2k-guideline "Atopic dermatitis" published in 2015. The reason for updating this chapter of the guideline were the current developments in the field of systemic therapy of atopic dermatitis. The agreed recommendations for systemic treatment in atopic dermatitis of the present guideline are based on current scientific data. Due to the approval of dupilumab for the treatment of moderate to severe atopic dermatitis, which cannot be treated sufficiently with topical drugs alone, this part of the guideline has now been adapted and newly consented. The indication for systemic therapy and the therapeutic response to topical and systemic treatment should be recorded and documented in a suitable form in clinic and practice. A standardized documentation of the indication for system therapy in atopic dermatitis can be recommended and is also part of the updated chapter of this guideline.
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http://dx.doi.org/10.1111/ddg.14371DOI Listing
January 2021

C3a and Its Receptor C3aR Are Detectable in Normal Human Epidermal Keratinocytes and Are Differentially Regulated via TLR3 and LL37.

J Innate Immun 2021 Jan 14:1-15. Epub 2021 Jan 14.

Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.

To study the molecular interplay between TLRs and complement representing ancient danger-sensing mechanisms, we examined the regulation of the C3a/anaphylatoxin C3a receptor (C3aR) axis in normal human epidermal keratinocytes (NHEKs) by treatment with different TLR ligands. Protein staining followed by flow cytometry revealed highly constitutive intracellular expression levels of the C3aR in NHEKs. Stimulation with Poly I:C up-regulated C3aR mRNA and intra- and extracellular expression in NHEKs which showed functional relevance by up-regulating CXCL10 and down-regulating C3 expression in response to C3a. mRNA and protein levels of C3 and protease cathepsin L (CTSL) that can cleave C3 were up-regulated by the TLR3 ligand Poly I:C. Enhanced intracellular expression levels of the biologically active C3 fragment (C3a), in response to TLR3 stimulation were also detectable in NHEKs. Cathelicidin antimicrobial peptide LL-37 potentiated Poly I:C-induced C3aR, C3, and CTSL up-regulation. In conclusion, we point to a role of TLR3 to promote up-regulation of C3aR, C3, and CTSL expression levels and generation of C3a. Our data provide evidence that local generation and activation of complement components as described for T cells or myeloid cells represent a scenario which may take place in a similar way in NHEKs.
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http://dx.doi.org/10.1159/000512547DOI Listing
January 2021

Severe allergic reactions to the COVID-19 vaccine - statement and practical consequences.

Allergol Select 2021 5;5:26-28. Epub 2021 Jan 5.

Allergy Center-Charité, Clinic for Dermatology, Venerology, and Allergology, Campus Charité Mitte, University Medicine Berlin, Germany.

No abstract available.
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http://dx.doi.org/10.5414/ALX02215EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787363PMC
January 2021

Biologics for atopic diseases: Indication, side effect management, and new developments.

Allergol Select 2021 5;5:1-25. Epub 2021 Jan 5.

Department of Dermatology and Allergy, Charité Universitätsmedizin, Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Comprehensive Allergy Center, Berlin, Germany.

With the advent of biologicals, more and more therapeutics are available that specifically address specific switch points in the pathomechanism of immunologically dominated diseases. Thus, the focus of diagnostics and therapy (precision medicine) is more on the individual disease characteristics of the individual patient. Regarding the different phenotypes of atopic diseases, severe asthma was the first entity for which biologicals were approved, followed by urticaria, and finally atopic dermatitis and chronic rhinosinusitis with nasal polyps. Experience in the treatment of severe bronchial asthma has shown that the intensity of the response to biological therapy depends on the quality of clinical and immunological phenotyping of the patients. This also applies to different diseases of the atopic form, as patients can suffer from several atopic diseases at the same time, each with different characteristics. Biologics are already emerging that may represent a suitable therapy for allergic bronchial asthma, which often occurs together with severe neurodermatitis, and chronic rhinosinusitis with nasal polyps. In practice, however, the question of possible combinations of biologicals for the therapy of complex clinical pictures of individual patients is increasingly arising. In doing so, the side effect profile must be taken into account, including hypersensitivity reactions, whose diagnostic and logistical management must aim at a safe and efficient therapy of the underlying disease. Increased attention must also be paid to biological therapy in pregnancy and planned (predictable) vaccinations as well as existing infections, such as SARS-CoV-2 infection. Before starting a biological therapy, the immune status should be checked with regard to chronic viral and bacterial infections and, if necessary, the vaccination status should be refreshed or missing vaccinations should be made up for before starting therapy. Currently, reliable data on the effect of biologicals on the immunological situation of SARS-CoV-2 infection and COVID-19 are not available. Therefore, research and development of suitable diagnostic methods for detection of immunologically caused side effects as well as detection of potential therapy responders and non-responders is of great importance.
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http://dx.doi.org/10.5414/ALX02197EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787364PMC
January 2021

Elevated NK-cell transcriptional signature and dysbalance of resting and activated NK cells in atopic dermatitis.

J Allergy Clin Immunol 2020 Dec 31. Epub 2020 Dec 31.

Department of Dermatology, Venereology, and Allergology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany. Electronic address:

Background: Altered quantities, activity, and composition of natural killer (NK) cells in blood as well as expression changes of genes involved in NK-cell function in skin lesions of patients with atopic dermatitis (AD) were recently reported.

Objectives: We sought to comprehensively analyze cutaneous NK-cell transcriptomic signatures in AD, and to examine changes under treatment.

Methods: We analyzed NK-cell signatures in skin transcriptome data from 57 patients with moderate to severe AD and 31 healthy controls. In addition, changes after 12 weeks of systemic treatment (dupilumab n = 21, cyclosporine n = 8) were analyzed. Deconvolution of leucocyte fractions was conducted. Immunofluorescence staining of NK cells was performed on paraffin-embedded skin sections.

Results: Immunofluorescence staining revealed a relatively high abundance of both NK cells and CD3CD56 cells in lesional as compared with nonlesional and healthy skin. Lesional and to a lesser extent nonlesional skin showed a strong upregulation of NK-cell markers together with a dysbalanced expression of inhibitory and activating receptors, which was not reverted under treatment. Digital cytometry showed a decrease in activated and an increase in resting NK cells in both lesional and nonlesional skin, which was reverted by both treatment with dupilumab and cyclosporine. The NK-cell transcriptomic signature remained upregulated after treatment, but there was a shift on the qualitative level, indicating a compositional change in NK-cell subsets toward CD56 NK cells.

Conclusions: Lesional AD skin shows a NK-cell dysregulation, which despite clinical improvement under systemic therapy was only partially reverted, and which may represent a yet underappreciated disease mechanism.
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http://dx.doi.org/10.1016/j.jaci.2020.11.022DOI Listing
December 2020

Unmet medical needs in the treatment of atopic dermatitis in infants: An Expert consensus on safety and efficacy of pimecrolimus.

Pediatr Allergy Immunol 2021 Apr 27;32(3):414-424. Epub 2020 Dec 27.

Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.

Atopic dermatitis (AD) is a common skin disease during infancy, which imposes a considerable burden on patients, their families, and the society, requiring effective treatment options that result in rapid and sustained symptom relief. Additionally, early treatment may prevent the development of atopic comorbidities by restoring the skin barrier. Currently, topical standard-of-care for AD in infants includes emollients and topical corticosteroids (TCS) to treat and reduce the risk of flares. However, only few have been approved for infants and long-term maintenance therapy with TCS is not indicated due to potential local and systemic side effects, including skin atrophy. Accordingly, the recently updated European guidelines for treatment of AD recommend topical calcineurin inhibitors (TCIs) for long-term use, treatment of sensitive skin areas, and for use in the pediatric population. Evidence on the use of TCIs for infants has almost been exclusively collected for pimecrolimus, with >4000 infants evaluated in clinical trials, consistently confirming that pimecrolimus is a safe and effective treatment for infants with AD. Nevertheless, its use is still restricted in most countries to children above the age of 2 years due to initial and mostly theoretical safety concerns. Based on a careful review of the available evidence of clinical trials, post-marketing surveillance, and epidemiological studies, an Expert Panel of European dermatologists and pediatric allergologists concluded that these safety concerns are no longer valid. Therefore, pimecrolimus offers a safe and effective alternative to TCS in infants aged 3 months and above, and labeling restrictions in this age group are no longer justified.
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http://dx.doi.org/10.1111/pai.13422DOI Listing
April 2021

[Recommendations when switching therapy from immunosuppressive drugs to dupilumab in patients with atopic dermatitis].

Hautarzt 2021 Apr;72(4):321-327

Klinik für Dermatologie und Allergologie, Ludwig-Maximilian-Universität München, München, Deutschland.

Based on new insights into the molecular pathogenesis of atopic dermatitis, a targeted anti-inflammatory therapy-dupilumab-has recently been approved as treatment alongside glucocorticoids and ciclosporin. Due to their pharmacology, neither glucocorticoids nor ciclosporin nor the off label used substances methotrexate, azathioprine and mycophenolic acid derivatives are suitable for long-term therapy. When switching therapy from small molecular substances to dupilumab, various factors should be considered. Both the specific cause of the change (ineffectiveness, adverse effects or contraindications) as well as the pharmacological conditions should be taken into account. Since there have been no specific clinical studies on this subject so far, the authors relied mainly on a literature search to draw up recommendations for practical everyday use.
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http://dx.doi.org/10.1007/s00105-020-04720-1DOI Listing
April 2021

Histamine 2 Receptor Agonism and Histamine 4 Receptor Antagonism Ameliorate Inflammation in a Model of Psoriasis.

Acta Derm Venereol 2020 Dec 9;100(19):adv00342. Epub 2020 Dec 9.

Institute for Pharmacology, Toxicology and Pharmacy, University of Veterinary Medicine Hannover, Hannover, Germany.

Psoriasis is a chronic inflammatory skin disorder characterized by hyperproliferative keratinocytes and immune cell infiltration into the skin, often accompanied by itch. Histamine, acting via histamine 1-4 receptors, is known to modulate immune responses in the skin and to induce itch. The aim of this study was to test the role of histamine 2 receptors and histamine 4 receptors in the imiquimod-induced psoriasis-like skin inflammation model. BALB/c mice were treated intraperitoneally with amthamine (histamine 2 receptor agonist), JNJ-39758979 (histamine 4 receptor antagonist), a combination of both, or vehicle twice daily in a preventive manner. Imiquimod was applied once daily onto the back skin for 10 consecutive days. Stimulation of histamine 2 receptors and blockade of histamine 4 receptors ameliorated imiquimod-induced skin inflammation. The combination of amthamine and JNJ-39758979 reduced skin inflammation even more pronounced, diminished epidermal hyperproliferation, and inhibited spontaneous scratching behaviour. A combination of histamine 2 receptor agonist and histamine 4 receptor antagonists could represent a new strategy for the treatment of psoriasis.
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http://dx.doi.org/10.2340/00015555-3674DOI Listing
December 2020

Systemic treatments in the management of atopic dermatitis: A systematic review and meta-analysis.

Allergy 2021 Apr 4;76(4):1053-1076. Epub 2020 Nov 4.

Center for Evidence-Based Healthcare, University Hospital Dresden, Dresden, Germany.

Background: As an evidence resource for the currently planned European Academy of Allergy and Clinical Immunology (EAACI) clinical practice guideline "systemic treatment of atopic dermatitis (AD)," we critically appraised evidence on systemic treatments for moderate-to-severe AD.

Methods: We systematically identified randomized controlled trials (RCTs) investigating the safety and efficacy of systemic treatments for AD up to February 2020. Primary efficacy outcomes were clinical signs, AD symptoms and health-related quality of life. Primary safety outcomes included cumulative incidence rates for (serious) adverse events. Trial quality was assessed applying the Cochrane Risk of Bias Tool 2.0. Meta-analyses were conducted where appropriate.

Results: 50 RCTs totalling 6681 patients were included. Trial evidence was identified for apremilast, azathioprine (AZA), baricitinib, ciclosporin A (CSA), corticosteroids, dupilumab, interferon-gamma, intravenous immunoglobulins (IVIG), mepolizumab, methotrexate (MTX), omalizumab, upadacitinib and ustekinumab. Meta-analyses were indicated for the efficacy of baricitinib [EASI75 RD 0.16, 95% CI (0.10;0.23)] and dupilumab [EASI75, RD 0.37, 95% CI (0.32;0.42)] indicating short-term (ie 16-week treatment) superiority over placebo. Furthermore, efficacy analyses of AZA and CSA indicated short-term superiority over placebo; however, nonvalidated scores were used and can therefore not be compared to EASI.

Conclusion: The most robust, replicated high-quality trial evidence is present for the efficacy and safety of dupilumab for up to 1 year in adults. Robust trial evidence was further revealed for AZA, baricitinib and CSA. Methodological restrictions led to limited evidence-based conclusions for all other systemic treatments. Head-to-head trials with novel systemic treatments are required to clarify the future role of conventional therapies.
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http://dx.doi.org/10.1111/all.14631DOI Listing
April 2021

Immunostimulatory biomaterials to boost tumor immunogenicity.

Biomater Sci 2020 Oct 2;8(20):5516-5537. Epub 2020 Sep 2.

Department of Chemical Engineering, University of Mississippi, University, MS, USA.

Cancer immunotherapy is exhibiting great promise as a new therapeutic modality for cancer treatment. However, immunotherapies are limited by the inability of some tumors to provoke an immune response. These tumors with a 'cold' immunological phenotype are characterized by low numbers of tumor-infiltrating lymphocytes, high numbers of immunosuppressive leukocytes (e.g. regulatory T cells, tumor-associated macrophages), and high production of immune-dampening signals (e.g. IL-10, TGF-β, IDO-1). Strategies to boost the aptitude of tumors to initiate an immune response (i.e. boost tumor immunogenicity) will turn 'cold' tumors 'hot' and augment the anti-tumor efficacy of current immunotherapies. Approaches to boost tumor immunogenicity already show promise; however, multifaceted delivery and immunobiology challenges exist. For instance, systemic delivery of many immune-stimulating agents causes off-target toxicity and/or the development of autoimmunity, limiting the administrable dose below the threshold needed to achieve efficacy. Moreover, once administered in vivo, molecules such as the nucleic acid-based agonists for many pattern recognition receptors are either rapidly cleared or degraded, and don't efficiently traffic to the intracellular compartments where the receptors are located. Thus, these nucleic acid-based drugs are ineffective without a delivery system. Biomaterials-based approaches aim to enhance current strategies to boost tumor immunogenicity, enable novel strategies, and spare dose-limiting toxicities. Here, we review recent progress to improve cancer immunotherapies by boosting immunogenicity within tumors using immunostimulatory biomaterials.
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http://dx.doi.org/10.1039/d0bm01183eDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837217PMC
October 2020

Repurposing of a Thromboxane Receptor Inhibitor Based on a Novel Role in Metastasis Identified by Phenome-Wide Association Study.

Mol Cancer Ther 2020 12 8;19(12):2454-2464. Epub 2020 Oct 8.

Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee.

Although new drug discoveries are revolutionizing cancer treatments, repurposing existing drugs would accelerate the timeline and lower the cost for bringing treatments to cancer patients. Our goal was to repurpose CPI211, a potent and selective antagonist of the thromboxane A-prostanoid receptor (TPr), a G-protein-coupled receptor that regulates coagulation, blood pressure, and cardiovascular homeostasis. To identify potential new clinical indications for CPI211, we performed a phenome-wide association study (PheWAS) of the gene encoding TPr, , using robust deidentified health records and matched genomic data from more than 29,000 patients. Specifically, PheWAS was used to identify clinical manifestations correlating with a single-nucleotide polymorphism (rs200445019), which generates a T399A substitution within TPr that enhances TPr signaling. Previous studies have correlated 200445019 with chronic venous hypertension, which was recapitulated by this PheWAS analysis. Unexpectedly, PheWAS uncovered an rs200445019 correlation with cancer metastasis across several cancer types. When tested in several mouse models of metastasis, TPr inhibition using CPI211 potently blocked spontaneous metastasis from primary tumors, without affecting tumor cell proliferation, motility, or tumor growth. Further, metastasis following intravenous tumor cell delivery was blocked in mice treated with CPI211. Interestingly, TPr signaling in vascular endothelial cells induced VE-cadherin internalization, diminished endothelial barrier function, and enhanced transendothelial migration by tumor cells, phenotypes that were decreased by CPI211. These studies provide evidence that TPr signaling promotes cancer metastasis, supporting the study of TPr inhibitors as antimetastatic agents and highlighting the use of PheWAS as an approach to accelerate drug repurposing.
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http://dx.doi.org/10.1158/1535-7163.MCT-19-1106DOI Listing
December 2020

The H R is highly expressed on eosinophils from AD patients and IL-4 upregulates expression and function via the JAK/STAT pathway.

Allergy 2021 Apr 7;76(4):1261-1264. Epub 2020 Oct 7.

Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1111/all.14599DOI Listing
April 2021

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

Histamine down-regulates the FCERI α-chain expression in human IL-4-activated M2 macrophages.

Allergy 2021 Apr 20;76(4):1250-1254. Epub 2020 Sep 20.

Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.

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http://dx.doi.org/10.1111/all.14576DOI Listing
April 2021

Formaldehyde 2% is not a useful means of detecting allergy to formaldehyde releasers- results of the ESSCA network, 2015-2018.

Contact Dermatitis 2021 Feb 16;84(2):95-102. Epub 2020 Oct 16.

Department of Dermatology, Chapel Allerton Hospital, Leeds, UK.

Background: Studies suggest that patch testing with formaldehyde releasers (FRs) gives significant additional information to formaldehyde 1% aq. and should be considered for addition to the European baseline series (EBS). It is not known if this is also true for formaldehyde 2% aq.

Objectives: To determine the frequency of sensitization to formaldehyde 2% aq. and co-reactivity with FRs. To establish whether there is justification for including FRs in the EBS.

Materials And Methods: A 4-year, multi-center retrospective analysis of patients with positive patch test reactions to formaldehyde 2% aq. and five FRs.

Results: A maximum of 15 067 patients were tested to formaldehyde 2% aq. and at least one FR. The percentage of isolated reactions to FR, without co-reactivity to, formaldehyde 2% aq. for each FR were: 46.8% for quarternium-15 1% pet.; 67.4% imidazolidinyl urea 2% pet.; 64% diazolidinyl urea 2% pet.; 83.3% 1,3-dimethylol-5, 5-dimethyl hydantoin (DMDM) hydantoin 2% pet. and 96.3% 2-bromo-2-nitropropane-1,3-diol 0.5% pet. This demonstrates that co-reactivity varies between FRs and formaldehyde, from being virtually non-existent in 2-bromo-2-nitropropane-1,3-diol 0.5% pet. (Cohen's kappa: 0, 95% confidence interval [CI] -0.02 to 0.02)], to only weak concordance for quaternium-15 [Cohen's kappa: 0.22, 95%CI 0.16 to 0.28)], where Cohen's kappa value of 1 would indicate full concordance.

Conclusions: Formaldehyde 2% aq. is an inadequate screen for contact allergy to the formaldehyde releasers, which should be considered for inclusion in any series dependant on the frequency of reactions to and relevance of each individual allergen.
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http://dx.doi.org/10.1111/cod.13691DOI Listing
February 2021