The pathogenesis of Hidradenitis Suppurativa

Author: John Frew

Frew, John, 2022 The pathogenesis of Hidradenitis Suppurativa, Flinders University, College of Medicine and Public Health

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Hidradenitis Suppurativa (HS) is a chronic inflammatory skin disease, the molecular pathogenesis of which is incompletely defined. A number of knowledge gaps in the field of HS exist. These include: an incomplete understanding of molecular disease pathogenesis; the lack of a clear pathogenic paradigm in line with the extant literature; a complete understanding of genetic basis of disease; the identification of factors

influencing therapeutic efficacy in HS, and the reasons underlying high placebo response rates in clinical trials. Additionally, there is an urgent need for the identification of novel therapeutic modalities in HS.

The publications included for presentation in this thesis address these six knowledge gaps. Bibliometric and Altimetric evidence supports the importance and high impact of these works to the field. The specific knowledge gaps each group of publications address are as follows:

1) Three publications with novel critical evaluation of the extant literature pertaining to inflammatory cytokines, immunohistochemical studies, as well as mechanisms of action of known therapeutic modalities.

2) Six publications, presenting critical discussion of poorly defined aspects of HS pathogenesis, namely- fibroblasts, complement and B cells, with the development of testable hypotheses about their role in HS. Additionally, novel molecular data regarding the inflammatory characteristics of epithelialized tunnels and inflammatory heterogeneity are presented. These data are integrated into an alternate ‘autoinflammatory’ pathogenic paradigm of disease pathophysiology. This paradigm is critically evaluated against the current follicular occlusion paradigm and data from the extant literature.

3) Five Publications, Discussing the limited and conflicting evidence surrounding genetic predisposition to disease- and examining the molecular basis of polymorphisms in the gamma secretase complex. Additionally, results of the first genotype-phenotype analysis in HS demonstrates that the current assumptions of the genetics of HS may be incorrect. In-silico analysis of gene expression data in HS suggest that specific gamma secretase substrates other than Notch may play a significant role in disease

pathogenesis and is an area which required further research.

4) Three Publications, identifying clinical predictors of clinical response to medical therapies. With regards to the efficacy of current treatment modalities, little is known in order to predict response to therapy. Given that predictive biomarkers in HS are still in their infancy, epidemiological data from recent Phase 3 clinical trials provide novel robust data to demonstrate that epithelialized tunnels, Body Mass Index and family

history contribute significantly to the clinical response to Adalimumab across a variety of

clinical outcome measures and endpoints.

5) Four Publications, critically evaluating the design and analysis of clinical trials in HS which have led to a number of unsuccessful therapeutics not progressing to the clinic. Important recommendations regarding biopsy definitions for clinical trials, the link between specific outcome measures and elevation in placebo response rates in HS, primary imputation methods in existing trials as well the first analysis of baseline variability of disease activity in HS which hold great significant for the design of future studies are presented.

6) Two publications describing two open-label clinical trials of Brodalumab in HS. Brodalumab is a novel therapeutic target for disease activity showing high levels of clinical response in these small pilot studies.

In summary, the twenty-three publications presented in this thesis critically evaluate and summarise the extant literature, provide novel evidence regarding the molecular pathogenesis and genetics of disease, identify variables associated with clinical response to current therapeutics, explain the reasons underlying elevated placebo response rates in HS clinical trials and present evidence of a novel therapeutic for use

in this disease.

Keywords: Hidradenitis Suppurativa, Dermatology, Inflammation, Pathogenesis, Acne Inversa

Subject: Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2022
School: College of Medicine and Public Health
Supervisor: A/Prof Gillian Marshman