Viewing Study NCT04133506



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Last Modification Date: 2024-10-26 @ 1:20 PM
Study NCT ID: NCT04133506
Status: ACTIVE_NOT_RECRUITING
Last Update Posted: 2019-10-21
First Post: 2019-10-17

Brief Title: PGE2IL-22 Pathway in Various Forms of Eczema
Sponsor: NHS Lothian
Organization: NHS Lothian

Study Overview

Official Title: Defining a PGE2 Pathway in Regulating Eczema
Status: ACTIVE_NOT_RECRUITING
Status Verified Date: 2024-09
Last Known Status: NOT_YET_RECRUITING
Delayed Posting: No
If Stopped, Why?: Not Stopped
Has Expanded Access: False
If Expanded Access, NCT#: N/A
Has Expanded Access, NCT# Status: N/A
Acronym: None
Brief Summary: Objectives Eczema is a chronic inflammatory skin condition characterised immunologically by T cellmediated inflammation The pathogenic mechanisms involved in its development are incompletely understood and targeted treatment options are limited The investigators will study the Prostaglandin E2 PGE2IL22IL17 pathway which plays an important role in murine model chronic skin inflammation The investigators wish to identify subtypes of human eczema in which this pathway may be involved and to determine whether manipulation of this pathway may offer effective new treatments

Design tissuecells techniques and measurements To address these objectives the investigators will measure the expression of IL22 IL17A and PGE2 synthases and receptors in skin biopsies from eczema and psoriasis patients using immunohistochemistry confirming this with RT-PCR IL22IL17 producing Tcells from peripheral blood and their skin-homing capability by ex-vivo cell culture and flow cytometry will be measured Deriving immune cells from skin biopsies using Villanovas technique1 the investigators will determine the T-cell response to PGE2 looking at PGE2 receptors and cytokine expression interrogating these cells by flow cytometry To determine the sequence and kinetics of activation of the PGE2IL22IL17 pathway the investigators will measure each immune mediator at specific time points by recruiting healthy volunteers inducing irritant and allergic contact dermatitis using dithranol and DNCB respectively The investigators will repeat the experiment dividing volunteers into two arms one pre-treated for one week with a non-specific prostaglandin inhibitor aspirin and the second with a placebo control
Detailed Description: Defining a specific IL-22-mediated pathway in regulating eczema i Introduction Overarching aim Eczema is a significant chronic skin disease yet the need for targeted treatments remains largely unmet In this study I will investigate the cellular mechanisms for how the IL-22 pathway contributes to skin inflammation in eczema and whether pharmacologic manipulation of this pathway might offer effective new treatments for this common disease

Main hypothesis and objectives I hypothesise that prostaglandin E2 PGE2 promotes eczema through activating IL-22 signalling and that blockade of PGE2 receptors EP2EP4 reduces eczema severity I will interrogate this hypothesis with three objectives 1 to examine whether IL22 overexpression in eczema patients is driven by endogenous PGE2 acting via EP2 and EP4 receptors 2 to determine whether this PGE2-IL-22 pathway is of particular importance in distinct subtypes of eczema and 3 to study whether blocking EP2EP4 receptors upstream of IL-22 and IL-17 will reduce eczema severity

Background and importance of research

Eczema is the most common chronic inflammatory skin disease with a rising prevalence in Western society placing an increasing economic burden on the health service3 It is increasingly being recognised as a heterogenous disease encompassing acute and chronic eczema and allergic contact dermatitis ACD It cumulatively affects over 4 of adults and 10 of children of whom 50 have persistent disease in adulthood The recent UK Translational Research Network in Dermatology priority setting exercise highlighted the burden created by this common and important diseaseThe requirement for a greater understanding of eczema pathogenesis according to subtype allowing patient stratification and the dearth of treatment options available are significant unmet needs This is in contrast with advances made in the development of biological therapies for psoriasis although refinement of these was also prioritised

Atopic eczema may predispose children to the atopic march and early effective treatment may reduce progression to asthma and hayfever in these patients Understanding the immune pathway in eczema may provide insight into inflammatory pathways generic to a range of diseases especially those arising at the environmental allergenepithelial interface

The mainstay of treatment for eczema over the last 50 years has been topical corticosteroids and latterly calcineurin inhibitors with the particular side effects of respectively skin thinning and carcinogenesis

Topical treatments are useful in mild disease but lack efficacy in those with moderate or severe eczema Systemic immunosuppressants are used for moderate and severe disease but these are blunderbuss drugs with no specificity for eczema and as a result can cause an extensive range of potentially serious adverse effects Dupilumab the first biologic treatment targeting dysregulated elements of the immune system in eczema has just received its European Marketing Authorisation approval The trial data are impressive and confirm that immune-targeting eczema treatments will produce a genuine paradigm shift in treatment of this disabling disease yet 30 of patients do not respond This highlights the importance of an increased understanding of immune dysfunction in eczema and the finding of new potentially druggable targets

Th22 cells are the predominant inflammatory infiltrative cells in chronic eczema lesional skin and IL-22 produced by Th22 and Th17 cells induces pathognomonic epidermal hyperplasia and also reduction of filaggrin expression leading to epithelial barrier disruption in a self-amplifying loop

Th22 infiltration correlates directly with eczema severity and IL22 gene expression is increased in atopic dermatitis suggesting IL-22 inhibition therapies as a specific target for eczema It is believed that IL-22 is as important a driver cytokine in eczema as IL-17 has been in psoriasis

Confirmation of the importance of IL-22 in driving eczema has been the phase 2a clinical trial showing successful treatment of severe eczema with an anti-lL-22 antibody fezakinumab

Chronic eczema and psoriasis share some immunological features In particular IL-17 and IL-22 are upregulated in both although IL-17 predominates in psoriasis while IL-22 predominates in chronic eczema Specific IL-17 antagonists are highly effective treatments for psoriasis but not eczema Both cytokines may be upregulated by PGE2 but shared pathways of induction are not fully understood

Therefore identification of molecules or pathways that specifically regulate IL-22IL-17 signaling will be particularly valuable because these approaches might offer new therapeutic strategies for treating eczema and also psoriasis

As a well-known inflammatory mediator PGE2 is one such molecule The investigators have published data from a completely separate from this study ie not results from this study the investigators have previously shown that PGE2 through its receptors EP2 and EP4 promotes IL-22IL-17 production from both innate and adaptive lymphocytes and mediates chronic inflammation in numerous tissues including skin The investigators have shown that by either pharmacologically inhibiting endogenous PGE2 production with a COX inhibitor indomethacin or by genetically blocking EP4 signaling hapten oxazolone OXA-induced chronic allergic contact dermatitis in mice is reduced and this is correlated with reduction of IL-22CD4 cells in skin-draining lymph nodes The phenotype of the imiquimod mouse model resembles eczema and psoriasis

PGE2IL23 as it impacts on IL-17 and IL-22 represents an elegant therapeutic target for both eczema and psoriasis in mice imiquimod mouse model with similar potential in man In a study which is completely separate to this not results of this study it was shown published data that genes related to IL-22IL-17 and PGE2 signaling pathways are up-regulated in close correlation in inflammatory skin in both eczema and psoriasis

Study Oversight

Has Oversight DMC: None
Is a FDA Regulated Drug?: False
Is a FDA Regulated Device?: False
Is an Unapproved Device?: None
Is a PPSD?: None
Is a US Export?: None
Is an FDA AA801 Violation?: None