The JAK-STAT pathway is involved in the signaling of multiple cytokines driving cutaneous inflammation in atopic dermatitis (AD). Janus kinase (JAK) inhibitors target individual receptor-associated kinases, thereby preventing the mediation of inflammatory signals. Several JAK inhibitors with varying mechanism of action, potency, and safety represent potential therapeutic options for AD in both topical and systemic application. The JAK1/2 selective JAK inhibitor baricitinib was the first substance from this class of drugs approved by the EMA for the systemic oral treatment of AD. The clinical development program of the JAK1 selective inhibitors upadacitinib and abrocitinib is finalized with positive results for AD. The PAN-JAK inhibitor delgocitinib was the first substance being approved for the treatment of AD (in Japan). This review article covers the rising data on investigational and approved JAK inhibitors in the context of the treatment of AD.
Atopic dermatitis (AD) is a chronic inflammatory skin disease, which is characteristically associated with intense pruritus and eczematous lesions. 1 Robert Willan, an English dermatologist, was the first to describe the disease in 1808. 2 In most countries, over 20% of children are affected at least once during a period of their lives. [3][4][5] Despite the fact that 85% of all cases manifest before the age of five, AD can occur lifelong and the prevalence of AD is still high in adulthood. 6-8 Surprisingly, recent data based on two birth cohorts revealed that only 38% of adult AD patients in the United Kingdom reported a childhood onset of symptoms. 9Patients suffering from AD are prone to viral and bacterial infections. 5 Staphylococcus aureus (S. aureus) infections are particularly common in AD patients, leading to superinfection. 10
Biomay AG Vienna funded this work. Disclosure of potential conflict of interest: P. Colombo's institute received BIOMAY AG for this work and his institute received patents from the Italian National Research Council for other work. A. Bonura's institute received patents from the Italian National Research Council for other work. The rest of the authors declare that they have no relevant conflicts of interest. 1022-34. 2. Valenta R, Campana R, Focke-Tejkl M, Niederberger V. Vaccine development for allergen-specific immunotherapy based on recombinant allergens and synthetic allergen peptides: lessons from the past and novel mechanisms of action for the future.
Background Understanding the complex orchestrated inflammation in atopic dermatitis (AD), one of the most common chronic inflammatory diseases worldwide, is essential for therapeutic approaches. However, a comparative analysis on the single‐cell level of the inflammation signatures correlated with the severity is missing so far. Methods We applied single‐cell RNA and T‐cell receptor (TCR) sequencing on immune cells enriched from skin biopsies and matched blood samples of AD in comparison with psoriasis (PS) patients. Results Clonally propagated skin‐derived T cells showed disease‐specific TCR motifs shared between patients which was more pronounced in PS compared to AD. The disease‐specific T‐cell clusters were mostly of a Th2/Th22 sub‐population in AD and Th17/Tc17 in PS, and their numbers were associated with severity scores in both diseases. Herein, we provide for the first time a list that associates cell type‐specific gene expression with the severity of the two most common chronic inflammatory skin diseases. Investigating the cell signatures in the patients´ PBMCs and skin stromal cells, a systemic involvement of type‐3 inflammation was clearly detectable in PS circulating cells, while in AD inflammatory signatures were most pronounced in fibroblasts, pericytes, and keratinocytes. Compositional and functional analyses of myeloid cells revealed the activation of antiviral responses in macrophages in association with disease severity in both diseases. Conclusion Different disease‐driving cell types and subtypes which contribute to the hallmarks of type‐2 and type‐3 inflammatory signatures and are associated with disease activities could be identified by single‐cell RNA‐seq and TCR‐seq in AD and PS.
Urticaria and angioedema are very common. Management of chronic urticaria subtypes, which usually persist for many years, is challenging. Recent years have demonstrated that targeting IgE with antibodies provides a safe and efficient treatment approach. Whilst several anti-IgE antibodies have been developed, omalizumab is currently the only one approved for use. International and national guidelines recommend its use after failure of antihistamines at standard and increased dose. Whilst not yet approved, many new anti-IgE approaches are currently being investigated in pre-clinical studies or clinical trials. This non-systematic focused review summarizes current knowledge of omalizumab and other anti-IgE biologics in chronic urticaria using data extracted from PubMed, Google Scholar and clinical trial databases, clinicaltrials.gov and clinicaltrials.eu. For adults, there is good evidence from randomized clinical trials and real-world data that symptomatic treatment with omalizumab is efficacious and safe in chronic spontaneous urticaria (CSU), whereas evidence in chronic inducible urticaria (CINDU) and special populations is limited. Easy-to-use tools to identify non-responders and predict the required duration of treatment have not been established yet. Phase 2 b results of ligelizumab have not only demonstrated efficacy and safety but also superiority to omalizumab. Indeed, there is preliminary evidence that omalizumab non- or partial responders benefit from ligelizumab. Whereas further development of quilizumab was discontinued, other approaches, eg UB-221 or DARPins are under investigation. Anti-IgE treatment with omalizumab represents a landmark in the treatment of chronic urticaria, with and without angioedema, and there is light on the horizon suggesting success may come with various next-generation anti-IgE approaches.
Background Atopic dermatitis (AD) and psoriasis represent two of the most common inflammatory skin diseases in developed countries. A hallmark of both diseases is T‐cell infiltration into the skin. However, it is still not clarified to what extent these infiltrating T cells are antigen‐specific skin‐homing T cells or unspecific heterogeneous bystander cells. Methods To elucidate this, T cells from lesional skin and from blood of 9 AD and 10 psoriasis patients were compared by receptor (TCR) sequencing. Therefore, peripheral blood mononuclear cells (PBMC) were cell‐sorted according to expression of the cutaneous leukocyte antigen (CLA) into skin‐homing (CLA+) and non‐skin‐homing (CLA−) subfractions. Aeroallergen‐specific T‐cell lines were grown from AD patients’ PBMC in parallel. Results Intra‐individual comparison of TCRB CDR3 regions revealed that clonally expanded T cells in skin lesions of both AD and psoriasis patients corresponded to skin‐homing circulating T cells. However, in psoriasis patients, these T‐cell clones were also detectable to a larger extent among CLA− circulating T cells. Up to 28% of infiltrating cells in AD skin were identified as allergen‐specific by overlapping TCR sequences. Conclusions Our data show that in line with the systemic nature of psoriasis, T‐cell clones that infiltrate psoriatic skin lesions do not exclusively possess skin‐homing ability and are therefore most probably specific to antigens that are not exclusively expressed or located in the skin. T cells driving AD skin inflammation appear to home nearly exclusively to the skin and are, to a certain extent, specific to aeroallergens.
Background: House dust mites (HDM) are among the most important sources for airborne allergens with high relevance for atopic diseases. Routine tests contain only 4 of 32 registered allergens of Dermatophagoides pteronyssinus. Clinical relevance and pathomechanistic properties of many allergens are not well understood.Objective: The association of several HDM allergens with allergic rhinitis, allergic asthma, and atopic dermatitis was investigated to identify allergens with biomarker potential and to transfer them into diagnostics.
Background: Allergic contact dermatitis caused by shoes is common and new relevant allergens have been identified.Objectives: To investigate the pattern of type IV sensitization in patients with suspected allergic contact dermatitis of the feet related to shoes as a presumed culprit trigger.Methods: Retrospective analysis of data of the Information Network of Departments of Dermatology (IVDK), 2009-2018.Results: Six hundred twenty-five patients with presumed shoe dermatitis were identified in a cohort of 119 417 patients. Compared to patients with suspected contact sensitization from other allergen sources (n = 118 792), study group patients were more frequently sensitized to potassium dichromate (10.8% vs 3.5%), colophony (7.2% vs 3.7%), mercaptobenzothiazole (MBT; 4.0% vs 0.6%), mercapto mix (4.6% vs 0.6%), and p-tert-butylphenol formaldehyde resin (1.6% vs 0.5%). Sensitizations to urea formaldehyde resin, melamine formaldehyde resin, glutaraldehyde, tricresyl phosphate, and phenyl glycidylether were rare. Moreover, reactions to compounds in the leather or textile dyes test series were scarce. Conclusion:A distinct sensitization pattern was observed in patients with suspected allergy to shoe materials. Although substances with low sensitization rates should be removed from the leather and shoe patch-test series, novel potential allergens should be added.
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