BACKGROUND Tralokinumab is a fully human monoclonal antibody that specifically neutralizes interleukin-13, a key driver of atopic dermatitis (AD). OBJECTIVES To evaluate the efficacy and safety of tralokinumab in combination with topical corticosteroids (TCS) in patients with moderate-to-severe AD who were candidates for systemic therapy. METHODS This was a double-blind, placebo plus TCS controlled phase III trial. Patients were randomized 2 : 1 to subcutaneous tralokinumab 300 mg or placebo every 2 weeks (Q2W) with TCS as needed over 16 weeks. Patients who achieved an Investigator's Global Assessment (IGA) score of 0/1 and/or 75% improvement in Eczema Area and Severity Index (EASI 75) at week 16 with tralokinumab were rerandomized 1 : 1 to tralokinumab Q2W or every 4 weeks (Q4W), with TCS as needed, for another 16 weeks. RESULTS At week 16, more patients treated with tralokinumab than with placebo achieved IGA 0/1: 38·9% vs. 26·2% [difference (95% confidence interval): 12·4% (2·9-21·9); P = 0·015] and EASI 75: 56·0% vs. 35·7% [20·2% (9·8-30·6); P < 0·001]. Of the patients who were tralokinumab responders at week 16, 89·6% and 92·5% of those treated with tralokinumab Q2W and 77·6% and 90·8% treated with tralokinumab Q4W maintained an IGA 0/1 and EASI 75 response at week 32, respectively. Among patients who did not achieve IGA 0/1 and EASI 75 with tralokinumab Q2W at 16 weeks, 30·5% and 55·8% achieved these endpoints, respectively, at week 32. The overall incidence of adverse events was similar across treatment groups. CONCLUSIONS Tralokinumab 300 mg in combination with TCS as needed was effective and well tolerated in patients with moderate-to-severe AD.

https://www.onlinelibrary.wiley.com/doi/epdf/10.1111/bjd.19573

Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial.

Hidradenitis suppurativa (HS) is a debilitating chronic inflammatory skin disease characterized by chronic abscess formation and development of multiple draining sinus tracts in the groin, axillae, and perineum. Using proteomic and transcriptomic approaches, we characterized the inflammatory responses in HS in depth, revealing immune responses centered on IFN-γ, IL-36, and TNF, with lesser contribution from IL-17A. We further identified B cells and plasma cells, with associated increases in immunoglobulin production and complement activation, as pivotal players in HS pathogenesis, with Bruton's tyrosine kinase (BTK) and spleen tyrosine kinase (SYK) pathway activation as a central signal transduction network in HS. These data provide preclinical evidence to accelerate the path toward clinical trials targeting BTK and SYK signaling in moderate-to-severe HS.

Contribution of plasma cells and B-cells to hidradenitis suppurativa pathogenesis.

Background Skin transcriptome studies in atopic dermatitis (AD) showed broad dysregulation as well as “improvement” under therapy These observations were mainly made in trials and based on microarray data Objectives To explore the skin transcriptome and the impact of systemic treatment in patients of the TREATgermany registry Methods Biopsies from 59 patients with moderate to severe AD before and 30 patients 12 weeks after start of systemic treatment (dupilumab n=22, cyclosporine n=8), and from 31 healthy controls were subjected to mRNA sequencing Differential expression, pathway enrichment, correlation, and co-expression network analysis were conducted Results Both lesional and non-lesional skin showed a stable “core” signature characterised by disturbed epidermal differentiation and activation of IL31-IL1 signalling A second dynamic signature showed progressive enrichment for type 2 inflammation, type 17 signalling and NK cell function Markers correlated with disease activity have functions in epidermal barrier properties and immune modulation IL4RA was among the top 3 central dysregulated genes Cyclosporine led to a more pronounced global transcriptome reversion and normalised Th17/IL23 signalling, whereas dupilumab led to a stronger increase of epidermal differentiation markers Both treatments strongly decreased type 2 markers, but overall the residual profile was still profoundly different from healthy skin Lower IL4RA and IL13, and high IL36A expression were related to a stronger clinical response to dupilumab Conclusion The AD core signature is characterised by dysregulation of genes related to keratinocyte differentiation and itch signalling A dynamic signature reflects progressive immune responses dominated by type-2 cytokines with an additional role of type 17 and NK cell signalling

Atopic dermatitis displays stable and dynamic skin transcriptome signatures

Pruritus as a Distinctive Feature of Type 2 Inflammation.

Atopic dermatitis (AD) is an immune-mediated inflammatory skin disease characterized by a predominant type 2 immune response. Type 2 immunity is driven by multiple cytokines, including interleukin (IL)‑4 and IL-13 that are considered central to AD pathogenesis and key therapeutic targets. The dual inhibition of these two cytokines or the selective inhibition of IL-13 proved elevated efficacy in treating AD, whereas the selective inhibition of IL-4 has been poorly investigated as IL-4 inhibiting agents did not show any advance in clinical development programs. This review describes the pathogenic role of IL-4 in AD and briefly resumes the main features of compounds selectively blocking IL-4.

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Targeting IL-4 for the Treatment of Atopic Dermatitis.

Background Although multiple studies have assessed molecular changes in chronic atopic dermatitis (AD) lesions, little is known about the transition from acute to chronic disease stages, and the factors and mechanisms that shape chronic inflammatory activity. Objectives We sought to assess the global transcriptome changes that characterize the progression from acute to chronic stages of AD. Methods We analyzed transcriptome changes in paired nonlesional skin, acute and chronic AD lesions from 11 patients and 38 healthy controls by RNA-sequencing, and conducted in vivo and histological assays to evaluate findings. Results Our data demonstrate that approximately 74% of the genes dysregulated in acute lesions remain or are further dysregulated in chronic lesions, whereas only 34% of the genes dysregulated in chronic lesions are altered already in the acute stage. Nonlesional AD skin exhibited enrichment of TNF, TH1, TH2, and TH17 response genes. Acute lesions showed marked dendritic-cell signatures and a prominent enrichment of TH1, TH2, and TH17 responses, along with increased IL-36 and thymic stromal lymphopoietin expression, which were further heightened in chronic lesions. In addition, genes involved in skin barrier repair, keratinocyte proliferation, wound healing, and negative regulation of T-cell activation showed a significant dysregulation in the chronic versus acute comparison. Furthermore, our data show progressive changes in vasculature and maturation of dendritic-cell subsets with chronicity, with FOXK1 acting as immune regulator. Conclusions Our results show that the changes accompanying the transition from nonlesional to acute to chronic inflammation in AD are quantitative rather than qualitative, with chronic AD having heightened TH2, TH1, TH17, and IL36 responses and skin barrier repair mechanisms. These findings provide novel insights and highlight underappreciated pathways in AD pathogenesis that may be amenable to therapeutic targeting.

Jingru Sun

Papers

Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses

IRAK2 Has a Critical Role in Promoting Feed-Forward Amplification of Epidermal Inflammatory Responses.