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The incidence of inflammatory bowel diseases (IBD) worldwide has resulted in a global public health challenge. Intestinal fibrosis leading to stricture formation and bowel obstruction is a frequent complication in Crohn's disease (CD), and the lack of anti‐fibrotic therapies makes elucidation of fibrosis mechanisms a priority. Progress has shown that mesenchymal cells, cytokines, microbial products, and mesenteric adipocytes are jointly implicated in the pathogenesis of intestinal fibrosis. This recent information puts prevention or reversal of intestinal strictures within reach through innovative therapies validated by reliable clinical trial endpoints. Here, we review the role of immune and non‐immune components of the pathogenesis of intestinal fibrosis, including new cell clusters, cytokine networks, host‐microbiome interactions, creeping fat, and their translation for endpoint development in anti‐fibrotic clinical trials. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic and relapsing, inflammatory skin disease characterized by impaired skin barrier function and immune system dysregulation that results in dryness, skin microbiome dysbiosis and intense pruritus. It is highly heterogeneous, and its management is demanding. Patients with AD are at greater risk of comorbidities such as attention‐deficit hyperactivity disorder as well as other atopic diseases. Early‐onset AD cases typically improve or resolve in late childhood; however, it is proposed that the prevalence of persistent or adult‐onset AD is higher than previously thought. Basic therapy consists of emollient application and trigger avoidance, and when insufficient, topical corticosteroids (TCS) are the first‐line treatment. However, corticophobia/steroid aversion and TCS side‐effects, particularly on sensitive skin areas, lead to low compliance and insufficient disease control. Several long‐ and short‐term randomized controlled and daily practice studies have demonstrated that topical calcineurin inhibitors, such as pimecrolimus, have similar anti‐inflammatory effects to low‐to‐medium strength TCS, reduce pruritus and improve the quality of life of patients. In addition, pimecrolimus does not cause skin atrophy, is steroid‐sparing and has a good safety profile, with no evidence for an increased risk of malignancies or skin infections. In general, pimecrolimus cream is well‐accepted and well‐tolerated, encouraging patient adherence and leading to its use by many physicians as a preferred therapy for children and sensitive skin areas. [ABSTRACT FROM AUTHOR]

Aim of the work: To identify the role of serum IL‐13, and its receptor subunit expressions as a serologic marker of rheumatoid arthritis (RA)‐associated ILD (RA‐ILD). Patients and Methods: Fifty RA patients with ILD and 50 RA patients without ILD were examined, in addition to 50 controls. Disease Activity Score in 28 joints (DAS‐28), the Health Assessment Questionnaire (HAQ), and medication history were evaluated. ESR, CRP, RF, Anti‐CCP, Serum Krebs von den Lungen‐6 (KL‐6), surfactant protein D (SP‐D) levels, Interleukin 13 and its receptors (IL‐13 Rα1 and L‐13 Rα2), and mRNA relative expression levels in peripheral blood mononuclear cells (PBMCs) were measured. High‐resolution computed tomography (HRCT) scores were used with all RA patients with interstitial lung disease. Results: Mean age, percent of male affection, duration of the disease, DAS28 and MHAQ were significantly higher in the RA–ILD group than in the RA–no ILD group. ESR, CRP, RF, anti‐CCP, serum KL‐6, SP‐D, IL‐13 levels, IL‐13 Rα1and IL‐13 Rα2 mRNA expressions were significantly increased in RA patients compared to controls; in addition, their levels were significantly higher in the RA–ILD group than in the RA–no ILD group. Serum IL‐13 levels and IL‐13 Rα1and IL‐13 Rα2 were positively correlated with RF, Anti‐CCP, KL‐6, SP‐D, and the HRCT score (P <.001). Conclusions: Serum IL‐13 and its receptor subunit expressions are useful biomarkers which can be used in detecting severity of the interstitial lung disease in RA patients. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a disease that can have a high impact on quality of life, especially due to itch and skin pain. This paper utilizes expertise from members of the International Society of Atopic Dermatitis (ISAD)/Oriented Patient‐Education Network in Dermatology (OPENED) task force to review the epidemiology, pathophysiology and exacerbating factors of itch and pain in atopic dermatitis. General principles of treatment are provided, as well as a more detailed evaluation of topical and systemic therapies. Educational and psychological approaches to itch and pain in atopic dermatitis are proposed, along with expert recommendations for the management of itch and pain in atopic dermatitis. [ABSTRACT FROM AUTHOR]

Since December 2019, coronavirus disease (COVID‐19) has rapidly swept the world. So far, more than 30 million people have been infected and nearly one million have died. Although the world is still in the stage of COVID‐19 pandemic, the treatment of new cases and critically ill patients is the focus of the current work. However, COVID‐19 patients lead to pulmonary fibrosis, such a serious threat to the prognosis of complications were also worthy of our attention. First of all, we proposed the possible mechanism of pulmonary fibrosis caused by SARS‐CoV‐2, based on the published data of COVID‐19 ((i) Direct evidence: pulmonary fibrosis was found in autopsy and pulmonary puncture pathology. (ii) Indirect evidence: increased levels of fibrosis‐related cytokines[transforming growth factor [TGF]‐ β, tumor necrosis factor [TNF]‐ α, interleukin [IL]‐6, etc] in peripheral blood of severe patients.) What is more, we summarized the role of three fibrosis‐related signaling pathways (TGF‐ β signal pathway, WNT signal pathway and YAP/TAZ signal pathway) in pulmonary fibrosis. Finally, we suggested the therapeutic value of two drugs (pirfenidone and nintedanib) for idiopathic pulmonary fibrosis in COVID‐19‐induced pulmonary fibrosis. Highlights: Severe COVID‐19 patients should pay attention to secondary pulmonary fibrosis after lung injuryTGF‐ β signal pathway, WNT signal pathway and YAP/TAZ signal pathway participated in pulmonary fibrosis caused by COVID‐19.3. Pirfenidone and Nintedanib may be the effective drugs for the treatment of pulmonary fibrosis caused by COVID‐19. [ABSTRACT FROM AUTHOR]

Mouse models for atopic dermatitis (AD) are an indispensable preclinical research tool for testing new candidate AD therapeutics and for interrogating AD pathobiology in vivo. In this Viewpoint, we delineate why, unfortunately, none of the currently available so‐called "AD" mouse models satisfactorily reflect the clinical complexity of human AD, but imitate more "allergic" or "irriant" contact dermatitis conditions. This limits the predictive value of AD models for clinical outcomes of new tested candidate AD therapeutics and the instructiveness of mouse models for human AD pathophysiology research. Here, we propose to initiate a rational debate on the minimal criteria that a mouse model should meet in order to be considered relevant for human AD. We suggest that valid AD models should at least meet the following criteria: (a) an AD‐like epidermal barrier defect with reduced filaggrin expression along with hyperproliferation, hyperplasia; (b) increased epidermal expression of thymic stromal lymphopoietin (TSLP), periostin and/or chemokines such as TARC (CCL17); (c) a characteristic dermal immune cell infiltrate with overexpression of some key cytokines such as IL‐4, IL‐13, IL‐31 and IL‐33; (d) distinctive "neurodermatitis" features (sensory skin hyperinnervation, defective beta‐adrenergic signalling, neurogenic skin inflammation and triggering or aggravation of AD‐like skin lesions by perceived stress); and (e) response of experimentally induced skin lesions to standard AD therapy. Finally, we delineate why humanized AD mouse models (human skin xenotransplants on SCID mice) offer a particularly promising preclinical research alternative to the currently available "AD" mouse models. [ABSTRACT FROM AUTHOR]

Background: Airway remodelling, which may include goblet cell hyperplasia / hypertrophy, changes in epithelial integrity, accumulation of extracellular matrix components, smooth muscle hypertrophy and thickening of the lamina reticularis, is a feature of severe asthma and contributes to the clinical phenotype. Objective: Within the U‐BIOPRED severe asthma study, we have assessed histological elements of airway remodelling and their relationship to computed tomography (CT) measures of proximal airway dimensions. Methods: Bronchial biopsies were collected from two severe asthma groups, one non‐smoker (SAn, n = 28) and one current/ex‐smoker (SAs/ex, n = 13), and a mild‐moderate asthma group (MMA, n = 28) classified and treated according to GINA guidelines, plus a healthy control group (HC, n = 33). Movat's pentachrome technique was used to identify mucin, elastin and total collagen in these biopsies. The number of goblet cells (mucin+) was counted as a percentage of the total number of epithelial cells and the percentage mucin epithelial area measured. The percentage area of elastic fibres and total collagen within the submucosa was also measured, and the morphology of the elastic fibres classified. Participants in the asthma groups also had a CT scan to assess large airway morphometry. Results: The submucosal tissue elastin percentage was higher in both severe asthma groups (16.1% SAn, 18.9% SAs/ex) compared with the HC (9.7%) but did not differ between asthma groups. There was a positive relationship between elastin and airway wall area measured by CT (n = 18–20, rho=0.544, p = 0.024), which also related to an increase in elastic fibres with a thickened lamellar morphological appearance. Mucin epithelial area and total collagen were not different between the four groups. Due to small numbers of suitable CT scans, it was not feasible to compare airway morphometry between the asthma groups. Conclusion: These findings identify a link between extent of elastin deposition and airway wall thickening in severe asthma. [ABSTRACT FROM AUTHOR]

Background: Endothelin‐1 (EDN1) can evoke histamine‐independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL‐25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model. Methods: We analyzed the mite‐induced AD‐like NC/Nga murine model, which was topically applied with bosentan or ethanol control every day for 3 weeks. We also subjected in vitro primary sensory neuron culture systems to nerve elongation and branching assays after EDN1 stimulation. Results: Topical application of bosentan significantly attenuated the development of mite‐induced AD‐like skin inflammation, dermatitis scores, ear thickness, scratching bouts, and serum level of thymus and activation‐regulated chemokine in NC/Nga mice. Bosentan application also significantly reduced the gene expression of Il13, Il17, and Ifng in the treated lesions. Histologically, the number of infiltrated dermal cells, the epidermal EDN1 expression, and the number of intraepidermal nerve fibers were significantly inhibited upon bosentan application. While EDN1 significantly elongated the neurites of dorsal root ganglion cells in a dose‐ and time‐dependent manner, bosentan treatment attenuated this. Conclusions: EDN1 plays a significant role in mite‐induced inflammation and itch. Topical bosentan is a potential protective candidate for AD. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a heterogeneic disease with a variety of treatments targeting different mechanisms. A multistate, mechanistic, mathematical model of IBD was developed in part 1 of this two‐part article series. In this paper, application of the model to predict response of key clinical biomarkers following different treatment options for Crohn's disease was explored. Five therapies, representing four different mechanisms of action, were simulated in the model and longitudinal profiles of key clinical markers, C‐reactive protein and fecal calprotectin were compared with clinical observations. Model simulations provided an accurate match with both central tendency and variability observed in biomarker profiles. We also applied the model to predict biomarker and clinical response in an experimental, combination therapy of existing therapeutic options and provide possible mechanistic basis for the increased response. Overall, we present a validated, modular, mechanistic model construct, which can be applied to explore key biomarkers and clinical outcomes in IBD. [ABSTRACT FROM AUTHOR]

Background: The anti‐interleukin 13 (IL‐13) monoclonal antibody lebrikizumab improves lung function in patients with moderate‐to‐severe uncontrolled asthma, but its effects on airway inflammation and remodelling are unknown. CLAVIER was designed to assess lebrikizumab's effect on eosinophilic inflammation and remodelling. Objective: To report safety and efficacy results from enrolled participants with available data from CLAVIER. Methods: We performed bronchoscopy on patients with uncontrolled asthma before and after 12 weeks of randomized double‐blinded treatment with lebrikizumab (n = 31) or placebo (n = 33). The pre‐specified primary end‐point was relative change in airway subepithelial eosinophils per mm2 of basement membrane (cells/mm2). Pre‐specified secondary and exploratory outcomes included change in IL‐13‐associated biomarkers and measures of airway remodelling. Results: There was a baseline imbalance in tissue eosinophils and high variability between treatment groups. There was no discernible change in adjusted mean subepithelial eosinophils/mm2 in response to lebrikizumab (95% CI, −82.5%, 97.5%). As previously observed, FEV1 increased after lebrikizumab treatment. Moreover, subepithelial collagen thickness decreased 21.5% after lebrikizumab treatment (95% CI, −32.9%, −10.2%), and fractional exhaled nitric oxide, CCL26 and SERPINB2 mRNA expression in bronchial tissues also reduced. Lebrikizumab was well tolerated, with a safety profile consistent with other lebrikizumab asthma studies. Conclusions & Clinical Relevance: We did not observe reduced tissue eosinophil numbers in association with lebrikizumab treatment. However, in pre‐specified exploratory analyses, lebrikizumab treatment was associated with reduced degree of subepithelial fibrosis, a feature of airway remodelling, as well as improved lung function and reduced key pharmacodynamic biomarkers in bronchial tissues. These results reinforce the importance of IL‐13 in airway pathobiology and suggest that neutralization of IL‐13 may reduce asthmatic airway remodelling. Clinical Trial Registration: NCT02099656. [ABSTRACT FROM AUTHOR]

Background: The airway epithelium plays an important role in wound repair, host defense and is involved in the immunopathogenesis of asthma. Genome wide association studies have described associations between ST2/Interleukin (IL)‐33 genes in asthma, but its role in bronchial epithelium is unclear. Methods: ST2 expression was examined in subjects with asthma and healthy controls in bronchial epithelium from biopsies (n = 27 versus n = 9) and brushings (n = 34 versus n = 20) by immunohistochemistry and RNA‐Seq. In human primary bronchial epithelial cells ST2 mRNA and protein expression were assessed by qPCR, flow cytometry, Western blotting, and immunofluorescence. IL‐33 function in epithelial cells was examined by intracellular calcium measurements, wound healing assays, and synthetic activation by gene array and ELISA. Results: Bronchial epithelial ST2 protein expression was significantly decreased in biopsies in subjects with asthma compared to healthy controls (P =.039). IL1RL1 gene expression in bronchial brushes was not different between health and disease. In vitro primary bronchial epithelial cells expressed ST2 and IL‐33 stimulation led to an increase in intracellular calcium, altered gene expression, but had no effect upon wound repair. Epithelial cells released sST2 spontaneously, which was reduced following stimulation with TNFα or poly‐IC. Stimulation by TNFα or poly‐IC did not affect the total ST2 expression by epithelial cell whereas surface ST2 decreased in response to TNFα, but not poly‐IC. Conclusion: In asthma, bronchial epithelium protein expression of ST2 is decreased. Our in vitro findings suggest that this decrease might be a consequence of the pro‐inflammatory environment in asthma or in response to viral infection. [ABSTRACT FROM AUTHOR]

Clinical data have shown that pulmonary interstitial fibrosis is likely to occur in the later stages of viral pneumonia. While viral infections are thought to cause chronic pulmonary interstitial inflammation and pulmonary fibrosis, it remains unclear if they promote pulmonary fibrosis by epithelial‐mesenchymal transition (EMT). In this study, human epithelial cell line A549 has been used to model the infection of the Epstein‐Barr virus (EBV) and the respiratory syncytial virus (RSV). Their differences were compared and the possible infection mechanisms analyzed by randomly assigning cells to one of five treatments. Exposure of the LMP1 is thought to be the key gene during EBV‐induced EMT in the A549 cells. Enzyme‐linked immunosorbent assay analysis revealed that the EBV infection was associated with the induction of a number of cytokines (interleukin‐8 [IL‐8], IL‐13, tumor necrosis factor‐α, and transforming growth factor‐β) and dexamethasone (DXM) could significantly prevent the phenotypic changes, and partly the mechanisms related with the IL‐13 pathway. Surprisingly, different results were seen with the RSV infection as the A549 cells still displayed an epithelial morphology but the levels of E‐cadherin, α‐SMA, vimentin, and fibronectin did not change. This is the first study demonstrating the different reactions induced by different viruses, and the protective effects of DXM on the EBV‐induced EMT in the A549 cells by partially inhibiting the IL‐13 pathway. These findings suggest a novel mechanism, by which DXM or anti‐IL‐13 may delay the progression of pulmonary fibrosis by preventing the progress of EBV‐induced EMT. [ABSTRACT FROM AUTHOR]

The 2019 Interactive Derma Academy (IDeA) meeting was held in Lisbon, Portugal, 10–12 May, bringing together leading dermatology experts from across Europe, the Middle East and Asia. Over three days, the latest developments and challenges in relation to the pathophysiology, diagnosis, evaluation and management of dermatological conditions were presented, with a particular focus on acne, atopic dermatitis (AD) and actinic keratosis (AK). Interesting clinical case studies relating to these key topics were discussed with attendees to establish current evidence‐based best practices. Presentations reviewed current treatments, potential therapeutic approaches and key considerations in the management of acne, AK and AD, and discussed the importance of the microbiome in these conditions, as well as the provision of patient education/support. It was highlighted that active treatment is not always required for AK, depending on patient preferences and clinical circumstances. In addition to presentations, two interactive workshops on the diagnosis and treatment of sexually transmitted infections/diseases (STIs/STDs) presenting to the dermatology clinic, and current and future dermocosmetics were conducted. The potential for misdiagnosis of STIs/STDs was discussed, with dermoscopy and/or reflectance confocal microscopy suggested as useful diagnostic techniques. In addition, botulinum toxin was introduced as a potential dermocosmetic, and the possibility of microbiome alteration in the treatment of dermatological conditions emphasized. Furthermore, several challenges in dermatology, including the use of lasers, the complexity of atopic dermatitis, wound care, use of biosimilars and application of non‐invasive techniques in skin cancer diagnosis were reviewed. In this supplement, we provide an overview of the presentations and discussions from the fourth successful IDeA meeting, summarizing the key insights shared by dermatologists from across the globe. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a highly pruritic, chronic inflammatory skin disease. The diagnosis is made using evaluated clinical criteria. Disease activity and burden are best measured with a composite score, assessing both objective and subjective symptoms, such as SCORing Atopic Dermatitis (SCORAD). AD management must take into account clinical and pathogenic variabilities, the patient's age and also target flare prevention. Basic therapy includes hydrating and barrier‐stabilizing topical treatment universally applied, as well as avoiding specific and unspecific provocation factors. Visible skin lesions are treated with anti‐inflammatory topical agents such as corticosteroids and calcineurin inhibitors (tacrolimus and pimecrolimus), which are preferred in sensitive locations. Topical tacrolimus and some mid‐potency corticosteroids are proven agents for proactive therapy, which is defined as the long‐term intermittent anti‐inflammatory therapy of frequently relapsing skin areas. Systemic anti‐inflammatory or immunosuppressive treatment is a rapidly changing field requiring monitoring. Oral corticosteroids have a largely unfavourable benefit–risk ratio. The IL‐4R‐blocker dupilumab is a safe, effective and licensed, but expensive, treatment option with potential ocular side‐effects. Other biologicals targeting key pathways in the atopic immune response, as well as different Janus kinase inhibitors, are among emerging treatment options. Dysbalanced microbial colonization and infection may induce disease exacerbation and can justify additional antimicrobial treatment. Systemic antihistamines (H1R‐blockers) only have limited effects on AD‐related itch and eczema lesions. Adjuvant therapy includes UV irradiation, preferably narrowband UVB or UVA1. Coal tar may be useful for atopic hand and foot eczema. Dietary recommendations should be patient‐specific, and elimination diets should only be advised in case of proven food allergy. Allergen‐specific immunotherapy to aeroallergens may be useful in selected cases. Psychosomatic counselling is recommended to address stress‐induced exacerbations. Efficacy‐proven 'Eczema school' educational programmes and therapeutic patient education are recommended for both children and adults. [ABSTRACT FROM AUTHOR]

Exposure to vesicants, including sulfur mustard and nitrogen mustard, causes damage to the epithelia of the respiratory tract and the lung. With time, this progresses to chronic disease, most notably, pulmonary fibrosis. The pathogenic process involves persistent inflammation and the release of cytotoxic oxidants, cytokines, chemokines, and profibrotic growth factors, which leads to the collapse of lung architecture, with fibrotic involution of the lung parenchyma. At present, there are no effective treatments available to combat this pathological process. Recently, much interest has focused on nutraceuticals, substances derived from plants, herbs, and fruits, that exert pleiotropic effects on inflammatory cells and parenchymal cells that may be useful in reducing fibrogenesis. Some promising results have been obtained with nutraceuticals in experimental animal models of inflammation‐driven fibrosis. This review summarizes the current knowledge on the putative preventive/therapeutic efficacy of nutraceuticals in progressive pulmonary fibrosis, with a focus on their activity against inflammatory reactions and profibrotic cell differentiation. [ABSTRACT FROM AUTHOR]

Copyright of Journal der Deutschen Dermatologischen Gesellschaft is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: Atopic dermatitis (AD) is a frequent, chronic remittent skin disease. The pathophysiology of AD has been increasingly understood within the last years, which may help to identify different endotypes suitable for defined therapies in the future. A patient‐oriented therapy considers phenotypical features in addition to genetic and biological markers. The most recent developments in biologics and small‐molecule drugs for AD treatment are presented in this article. These molecules, if approved, could change the perspectives for future therapies. Dupilumab is the first approved biologic for the treatment of moderate to severe atopic dermatitis in adolescence and adulthood and has led to a significant improvement in the treatment of this chronic disease. In the present article we present real‐life data on the efficacy of dupilumab in adult dermatitis patients. We also discuss other data relevant to the use of dupilumab, and address open questions important for the standard care of atopic dermatitis patients. [ABSTRACT FROM AUTHOR]

While there has been much interest in using biomarkers to select patients for particular targeted therapies, there has been much less attention paid to how these biomarkers change in patients once treatment begins. This is an area of great interest to practising clinicians, especially respiratory physicians and allergists who manage severe asthma. In this article, we review monoclonal antibodies and related targeted therapies, especially those that are currently available or in late stage clinical trials, focussing on the differential effects such agents have on biomarkers in widespread clinical practice such as eosinophils, FeNO and total IgE. Serial measurements of biomarkers can be useful in determining whether a particular targeted therapy is having its expected biological effect and invaluable in assessing the reasons for treatment failure should that occur. [ABSTRACT FROM AUTHOR]

Copyright of Journal der Deutschen Dermatologischen Gesellschaft is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Summary: The COVID‐19 pandemic caused by SARS‐CoV‐2 has far‐reaching direct and indirect medical consequences. These include both the course and treatment of diseases. It is becoming increasingly clear that infections with SARS‐CoV‐2 can cause considerable immunological alterations, which particularly also affect pathogenetically and/or therapeutically relevant factors. Against this background we summarize here the current state of knowledge on the interaction of SARS‐CoV‐2/COVID‐19 with mediators of the acute phase of inflammation (TNF, IL‐1, IL‐6), type 1 and type 17 immune responses (IL‐12, IL‐23, IL‐17, IL‐36), type 2 immune reactions (IL‐4, IL‐13, IL‐5, IL‐31, IgE), B‐cell immunity, checkpoint regulators (PD‐1, PD‐L1, CTLA4), and orally druggable signaling pathways (JAK, PDE4, calcineurin). In addition, we discuss in this context non‐specific immune modulation by glucocorticosteroids, methotrexate, antimalarial drugs, azathioprine, dapsone, mycophenolate mofetil and fumaric acid esters, as well as neutrophil granulocyte‐mediated innate immune mechanisms. From these recent findings we derive possible implications for the therapeutic modulation of said immunological mechanisms in connection with SARS‐CoV‐2/COVID‐19. Although, of course, the greatest care should be taken with patients with immunologically mediated diseases or immunomodulating therapies, it appears that many treatments can also be carried out during the COVID‐19 pandemic; some even appear to alleviate COVID‐19. [ABSTRACT FROM AUTHOR]

Omalizumab is a monoclonal antibody, targeting Fc receptor of IgE, approved for the treatment of allergic asthma and chronic spontaneous urticaria. Its utility in atopic dermatitis appears controversial from data in literature since the molecule is well tolerated but it seems less effective than other medications used in adult patients (eg, Dupilumab). At present, the use of Dupilumab is not approved in pediatric patients therefore there are no second level treatments available in this age group. Here we report two clinical cases of patients (15 and 16 years old) suffering from both atopic dermatitis and asthma, treated with Omalizumab. Our experience suggests that atopic eczema of young patients with allergic comorbidities can benefit from asthma treatment with Omalizumab observing improvement on both conditions. [ABSTRACT FROM AUTHOR]

There has been extensive progress in understanding the cellular and molecular mechanisms of inflammation and immune regulation in allergic diseases of the skin and lungs during the last few years. Asthma and atopic dermatitis (AD) are typical diseases of type 2 immune responses. interleukin (IL)‐25, IL‐33, and thymic stromal lymphopoietin are essential cytokines of epithelial cells that are activated by allergens, pollutants, viruses, bacteria, and toxins that derive type 2 responses. Th2 cells and innate lymphoid cells (ILC) produce and secrete type 2 cytokines such as IL‐4, IL‐5, IL‐9, and IL‐13. IL‐4 and IL‐13 activate B cells to class‐switch to IgE and also play a role in T‐cell and eosinophil migration to allergic inflammatory tissues. IL‐13 contributes to maturation, activation, nitric oxide production and differentiation of epithelia, production of mucus as well as smooth muscle contraction, and extracellular matrix generation. IL‐4 and IL‐13 open tight junction barrier and cause barrier leakiness in the skin and lungs. IL‐5 acts on activation, recruitment, and survival of eosinophils. IL‐9 contributes to general allergic phenotype by enhancing all of the aspects, such as IgE and eosinophilia. Type 2 ILC contribute to inflammation in AD and asthma by enhancing the activity of Th2 cells, eosinophils, and their cytokines. Currently, five biologics are licensed to suppress type 2 inflammation via IgE, IL‐5 and its receptor, and IL‐4 receptor alpha. Some patients with severe atopic disease have little evidence of type 2 hyperactivity and do not respond to biologics which target this pathway. Studies in responder and nonresponder patients demonstrate the complexity of these diseases. In addition, primary immune deficiency diseases related to T‐cell maturation, regulatory T‐cell development, and T‐cell signaling, such as Omenn syndrome, severe combined immune deficiencies, immunodysregulation, polyendocrinopathy, enteropathy, X‐linked syndrome, and DOCK8, STAT3, and CARD11 deficiencies, help in our understanding of the importance and redundancy of various type 2 immune components. The present review aims to highlight recent advances in type 2 immunity and discuss the cellular sources, targets, and roles of type 2 mechanisms in asthma and AD. [ABSTRACT FROM AUTHOR]

Background: Effective treatment for severe asthma is a significant unmet need. While eosinophilic inflammation caused by type 2 cytokines is responsive to corticosteroid and biologic therapies, many severe asthmatics exhibit corticosteroid‐unresponsive mixed granulocytic inflammation. Objective: Here, we tested the hypothesis that the pro‐allergic cytokine, IL‐13, can drive both corticosteroid‐sensitive and corticosteroid‐resistant responses. Results: By integration of in vivo and in vitro models of IL‐13–driven inflammation, we identify a role for the epidermal growth factor receptor (EGFR/ERBB1) as a mediator of corticosteroid‐unresponsive inflammation and bronchial hyperresponsiveness driven by IL‐13. Topological data analysis using human epithelial transcriptomic data from the U‐BIOPRED cohort identified severe asthma groups with features consistent with the presence of IL‐13 and EGFR/ERBB activation, with involvement of distinct EGFR ligands. Our data suggest that IL–13 may play a dual role in severe asthma: on the one hand driving pathologic corticosteroid‐refractory mixed granulocytic inflammation, but on the other hand underpinning beneficial epithelial repair responses, which may confound responses in clinical trials. Conclusion and Clinical Relevance: Detailed dissection of those molecular pathways that are downstream of IL‐13 and utilize the ERBB receptor and ligand family to drive corticosteroid‐refractory inflammation should enhance the development of new treatments that target this sub‐phenotype(s) of severe asthma, where there is an unmet need. [ABSTRACT FROM AUTHOR]

The rapidly increasing incidence of inflammatory bowel disease (IBD) in South America, eastern Europe, Asia, and Africa has resulted in a global public health challenge. Intestinal fibrosis is a common complication in patients with long‐term IBD, which may develop into stenosis and subsequent obstruction. Hitherto, the origin of IBD is unclear and several factors may be involved, including genetic, immune, environmental and microbial influences. Little is known about how the recurrent inflammation in patients with IBD develops into intestinal fibrosis and currently, there is no suitable treatment to reverse intestinal fibrosis in these patients. Here, we review the role of immune components in the pathogenesis of IBD and intestinal fibrosis, including cytokine networks, host–microbiome interactions, and immune cell trafficking. [ABSTRACT FROM AUTHOR]

A growing number of clinical trials of biological and systemic therapies have been conducted within adult atopic dermatitis (AD). No study has yet examined and meta‐analysed the pooled placebo response in AD. We performed a systematic review and meta‐analysis to examine the placebo response in clinical trials evaluating the effect of systemic and biological therapies in adult AD and compared it to results from clinical trials in psoriasis. Two screeners independently searched the databases ClinicalTrials.gov, Embase, Pubmed and Web of Science. A total of 2058 articles were identified, of which 78 were full‐text reviewed. Overall, 25 trials were included in the qualitative analysis, of which 24 were further included in the quantitative analysis. At 12‐week follow‐up, EASI50, EASI75 and EASI90 placebo responses were 39.9% [95% confidence interval (CI), 36.7–43.2], 20.9% (95% CI, 18.2–23.8) and 9.0% (95% CI, 6.7–11.6), respectively. At week 12, the pooled proportion of placebo‐treated AD patients that obtained EASI50, EASI75 and EASI90 was significantly higher than the pooled proportion of placebo‐treated psoriasis patients obtaining PASI50, PASI75 and PASI90 (P < 0.05). Our findings emphasize the fluctuating nature of AD and show that correct and consistent use of topical treatments strongly reduces disease severity. [ABSTRACT FROM AUTHOR]

Background: The Atopic Dermatitis (AD) TREATgermany registry was initiated by the German Society for Dermatology (DDG) in 2011 to evaluate the 'real‐life' situation of health care for patients with AD. Objectives: Interim data analysis on baseline characteristics as well as current and prescribed systemic treatments of the TREATgermany registry patients. Methods: Patients (≥18 years) with moderate‐to‐severe AD [objective (o)SCORAD > 20], or with current or previous anti‐inflammatory systemic treatment for AD within 24 months, were included and are followed up over at least 24 months. To assess clinical signs, the eczema area severity index (EASI, 0–72), the oSCORAD (0–83) and the Investigator Global Assessment (IGA; 6‐point scale) were used. The disease severity was globally scored by the patients [Patient Global Assessment (PGA); six‐step Likert scale]. Disease symptoms were assessed by the patient‐oriented eczema measure (POEM, 0–28) and numeric rating scales (NRS, 0–10). Health‐related quality of life was measured using the dermatological life quality index (DLQI, 0–30). Results: A total of 612 patients were recruited across 32 sites between 06/2016 and 01/2019 (mean age: 42.6 ± 14.2 years; mean oSCORAD: 40.8 ± 16.3). The mean POEM score was 16.3 ± 7.5. Pruritus was rated highest among subjective symptoms (NRS: 5.4 ± 2.7). The mean DLQI value was 11.3 ± 7.5. The frequency of arterial hypertension was lower (20.8%) compared with the general population, whilst this was higher for depression (10%). More than 60% of the patients had received systemic glucocorticosteroids, and 36.8% had received cyclosporine A prior to inclusion. Dupilumab was the leading substance documented as either 'current' (12.1%) or 'prescribed' (31.4%) at baseline. Conclusions: These 'real‐life' data clearly demonstrate the substantial disease burden. Most of TREATgermany patients were already treated with or prescribed dupilumab at baseline. Moreover, current findings indicate the urgent need for further alternative agents in order to achieve a perceptible improvement of quality of life of patients with moderate‐to‐severe AD. [ABSTRACT FROM AUTHOR]

The mammalian gastrointestinal compartment is colonised by millions of microorganisms that have a central influence on human health. Intestinal homeostasis requires a continuous dialogue between the commensal bacteria and intestinal immune cells. While interactions between host and commensal bacteria are normally beneficial, allowing training and functional tuning of immune cells, dysregulated immune system–microbiota crosstalk can favour the development of chronic inflammatory diseases, as it is the case for inflammatory bowel disease (IBD). Natural killer T (NKT) cells, which recognise CD1‐restricted microbial and self‐lipids, contribute to the regulation of mucosal immunity by controlling intestinal homeostasis and participating in the development of IBD. Here, we provide an overview of the recently identified pathways underlying the crosstalk between commensal bacteria and NKT cells and discuss the effect of these interactions in intestinal health and disease. [ABSTRACT FROM AUTHOR]

Biologicals have transformed the way of treatment of many immune-mediated disorders including cancer, autoimmune, and allergic diseases.[[1]] Biologicals and the understanding of their impact on diseases is a rapidly evolving field in which emerging important questions arise. Therefore, current EAACI AIT guidelines for HDM-driven allergic asthma do not recommend co-administration of biologicals with HDM AIT.[5] Large clinical trials with other biologicals are currently under development. EAACI Guidelines on biologicals will be of great relevance to move forward and consolidate the concept of personalized medicine and precision health for allergic diseases and asthma. [Extracted from the article]

Allergies are typically endemic, complex and heterogeneous diseases with a high impact at quality of life. Mechanistically, type 2 immune responses involving eosinophil and basophil granulocytes, mast cells and humoral factors such as IgE are key drivers of allergic diseases. Fighting allergic diseases knows three strategies: prevention, symptomatic and causative therapy. While remarkable progress was made in understanding molecular events in allergies as a prerequisite for effective prevention and desensitization, this review article focuses on the most efficient symptomatic treatments—that is using more and more specific antibodies neutralizing particular immune pathways. We highlight and classify recent and upcoming developments in the three prototype chronic allergic diseases allergic asthma, chronic spontaneous urticaria and atopic eczema. In all three examples, biologics such as dupilumab or omalizumab become reliable and efficient therapeutic options. Finally, we give an outlook how a diagnostic and therapeutic workflow might look like in the near future for these three major burdens of society. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic inflammatory skin disease and sometimes is a tough challenge for physicians. We previously reported that in Th2 environment, the production and secretion of thymic stromal lymphopoietin (TSLP) from human keratinocytes was inhibited by recombinant heat shock protein 70 (rHSP70). The present study assessed the therapeutic effectiveness of rHSP70 in a mouse model of AD. An experimental model of AD was reproduced by systemic sensitization and local epicutaneous challenge with ovalbumin (OVA). Treatment of rHSP70 was performed by subcutaneous administration. The levels of OVA‐specific IgE, as well as cytokines, were detected by ELISA. Skin samples from patch areas were also taken for histologic examination. Injection of rHSP70 improved the histologic picture by reducing the thickness of epidermis and allergic inflammation. Skin sonography revealed rHSP70 ameliorated skin remodeling. rHSP70 also significantly decreased the protein expression of TSLP of skin from patch areas. Furthermore, in ex vivo studies also showed group of rHSP70 treatment decreased IL‐13, RANTES, MIP‐1β and increased IFN‐γ secreted from splenocytes stimulated with OVA. The rHSP70 intervention in the mouse model of AD reduced the skin expression of TSLP and attenuated the clinical appearance of OVA‐induced AD mice. The effect was achieved by suppressed Th2 immune response in injected skin tissue and enhanced systemic Th1 immune response. These results suggest that rHSP70 have potential as a promising protein for the treatment of AD. [ABSTRACT FROM AUTHOR]

The identification of sputum eosinophilia indicating corticosteroid responsiveness in subjects with severe asthma heralded the beginning of phenotyping asthmatic subjects based on airways inflammation. Since then, the heterogeneity of severe asthma has been explored and the importance of immunobiology has come sharply into focus with the identification of the key type‐2 cytokine pathways driving eosinophilic inflammation. The development of molecules targeting these type‐2 pathways has transformed severe asthma treatment, but necessitates robust clinical evaluation, biomarker profiling and assessment of comorbid factors to identify subjects most likely to benefit from these therapies. It has also become clear that targeting these pathways does not eradicate asthma symptoms and exacerbation risk; further work is needed to clarify underlying non‐type‐2 mechanisms in severe asthma pathways and possible therapeutic targets. This review addresses progress to date in clinical assessment and management of severe asthma and some of the challenges and unmet needs in severe asthma to achieve the goal of delivering individualized patient care. [ABSTRACT FROM AUTHOR]

With the rapid development of new, targeted therapies for the treatment of moderate/severe atopic dermatitis, it is opportune to review the available conventional systemic agents. We assess the published evidence for systemic therapies for atopic dermatitis and amalgamate this with real‐world experience. Discussions are centred on when systemic therapy should be considered, which drug(s), what dose, how to sequence or combine these therapies, how long they should be continued for and what is considered success. [ABSTRACT FROM AUTHOR]

Itch is a defining symptom of atopic dermatitis. Crosstalk between keratinocytes, the immune system and non‐histaminergic sensory nerves is responsible for the pathophysiology of chronic itch in atopic dermatitis. An expanding understanding of the contribution of the nervous system and its interaction with immune pathways in atopic itch are helping to identify new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Hand eczema is a highly prevalent, multietiological disease with a wide spectrum of severity and chronicity. The treatment of hand eczema, especially in severe and chronic cases, is a challenge to the dermatologist requiring not only diagnostic and therapeutic, but also excellent patient communication skills. This review discusses the spectrum of therapeutic options for hand eczema, the evidence for their efficacy and safety, and proposes a stepwise approach of intensity of treatment depending on disease severity and chronicity. In the near future, hand eczema patients may benefit from new therapeutic principles such as biologics for the treatment of atopic eczema and topical Janus Kinase inhibitors. [ABSTRACT FROM AUTHOR]

Pruritus is one of the most common complaints among patients referred to a dermatology clinic. "Chronic generalized pruritus" is described as the sensation of itching on the entire body surface, which lasts at least 6 or more weeks. This symptom can be a disabling phenomenon for patients and may sometimes interfere with daily activities such as sleep. If specific dermatological findings are observed, the physician easily comes to a diagnosis and treats the condition, whereas, when primary lesions are not detected, the diagnosis can become challenging, and some patients have to undergo extensive evaluations. The association between some systemic disorders and chronic generalized pruritus is widely known and confirmed. Many infections have been associated with pruritus, but few are considered to cause chronic generalized pruritus without any characteristic skin lesions. We aimed to gather all the available data on infectious causes of chronic generalized pruritus with no diagnostic cutaneous lesions to assist fellow physicians in the process of evaluation of these challenging cases. [ABSTRACT FROM AUTHOR]

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Summary: Our understanding of the mechanisms underlying atopic dermatitis has been instrumental in the development of novel pharmacological agents. Worldwide, more than seventy companies are currently developing at least one new drug for the treatment of atopic dermatitis. Based on our current understanding of the pathophysiology of the disease, the present review article highlights the most important novel therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Chronic rhinosinusitis (CRS) is the downstream manifestation of heterogeneous pathophysiologic mechanisms leading to chronic sinonasal inflammation. Traditional grouping of patients by symptoms or clinical findings/phenotypes is being replaced by classification of CRS patients based on the underlying pathophysiologic mechanisms: endotypes. Objective of Review: To provide an up‐to‐date review on the current knowledge of CRS endotypes with a focus on how the pathophysiologic mechanisms defined by each endotype may be targeted therapeutically. Special emphasis is placed on the clinical relevance of the material and how it may inform the current practice of otolaryngologists. Type of Review: A systematic review of contemporary literature review focusing on the latest studies examining the role of endotypes in the management and treatment of CRS. Search Strategy: A MEDLINE and PubMed Central search were undertaken to perform this review using the keywords "Endotype" and "Sinusitis." Evaluation Method: Articles containing the keywords, as well as the references of those articles, were then examined for relevance. Results: The endotypes for CRS are often defined based on the balance of T‐helper cell patterns of inflammation and can be grouped into Th2 and non‐Th2 inflammation. These groups have shown a variable response to medical and surgical therapy, demonstrating that existing mainstream treatments can be tailored to patients with specific endotypes. The inflammatory mediators of Th2 inflammation, IL‐4, IL‐5 and IL‐13 as well as IgE, are targeted by available biologic drugs that can be used for treatment of refractory disease. Conclusions: Increased understanding of CRS endotypes has led to the identification of biomarkers that define these endotypes and act as targets for potential therapeutics. Increasing knowledge about characteristics associated with these endotypes and their responses to treatments, including both established mainstream CRS treatments and novel biologic medications, has allowed incorporation of CRS endotypes into the current clinical decision‐making. Treatment of CRS patients based on consideration of their endotypes is therefore not only presently possible but may improve clinical outcomes of those patients as well. [ABSTRACT FROM AUTHOR]

Inflammation, structural, and functional abnormalities within the airways are key features of asthma. Although these processes are well documented, their expression varies across the heterogeneous spectrum of asthma. Type 2 inflammatory responses are characterized by increased levels of eosinophils, FeNO, and type 2 cytokines in blood and/or airways. Presently, type 2 asthma is the best‐defined endotype, typically found in patients with allergic asthma, but surprisingly also in nonallergic patients with (severe) asthma. The etiology of asthma with non‐type 2 inflammation is less clear. During the past decade, targeted therapies, including biologicals and small molecules, have been increasingly integrated into treatment strategies of severe asthma. These treatments block specific inflammatory pathways or single mediators. Single or composite biomarkers help to identify patients who will benefit from these treatments. So far, only a few inflammatory biomarkers have been validated for clinical application. The European Academy of Allergy & Clinical Immunology Task Force on Biomarkers in Asthma was initiated to review different biomarker sampling methods and to investigate clinical applicability of new and existing inflammatory biomarkers (point‐of‐care) to support diagnosis, targeted treatment, and monitoring of severe asthma. Subsequently, we discuss existing and novel targeted therapies for asthma as well as applicable biomarkers. [ABSTRACT FROM AUTHOR]

Background: Allergen‐specific immunotherapy (AIT) is the only causal treatment for allergy. However, success rates vary depending on the type of allergy and disease background of the patient. Hence, strategies targeting an increased therapeutic efficacy are urgently needed. Here, the effects of blockade of IL‐4 and IL‐13 signaling on different phases of AIT were addressed. Methods: The impact of the recombinantly produced IL‐4 and IL‐13 antagonist IL‐4 mutein (IL‐4M) on allergic sensitization and AIT outcome in experimental allergic asthma were analyzed in a murine model. The effects of IL‐4M administration were assessed prior/during sensitization, immediately after AIT under allergen challenge, and two weeks post‐treatment. Results: Intervention with IL‐4M prior/during sensitization led to strong induction of IgG1, IgG2a, IgG2b, and IgG3, decrease of specific and total IgE, as well as of IL‐5 in serum. Similar effects on the serum immunoglobulin levels were observed immediately after IL4M‐supplemented AIT during allergen challenge. Additionally, IL4M markedly suppressed type‐2 cytokine secretion of splenocytes beyond the effect of AIT alone. These effects were equaled to those of AIT alone two weeks post‐treatment. Intriguingly, here, IL‐4M induced a sustained decrease of Th2‐biased Tregs (ST2+FOXP3+GATA3intermediate). Conclusions: IL‐4 and IL‐13 blockade during experimental AIT demonstrates beneficial effects on immunological key parameters such as immunoglobulin and cytokine secretion immediately after AIT. Although two weeks later these effects were dropped to those of AIT alone, the number of potentially disease‐triggering Th2‐biased Tregs was further significantly decreased by IL‐4M treatment. Hence, IL‐4/IL13‐targeting therapies prime the immune memory in therapy success‐favoring manner. [ABSTRACT FROM AUTHOR]