Student Theses and Dissertations

Date of Award

2021

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

RU Laboratory

Krueger Laboratory

Abstract

Hidradenitis suppurativa (HS) is an inflammatory skin disease manifesting in painful nodules and abscesses, and malodorous draining tunnels in more advanced disease. Effective treatment options remain limited, with Tumor Necrosis Factor inhibitor adalimumab remaining the only approved biologic despite its limited efficacy. The development of novel therapeutics is impeded by our lack of understanding of disease pathogenesis and an absence of standardized approaches to study HS. In this thesis, we establish a translational approach to characterize HS by examining nonlesional, perilesional and lesional HS skin in comparison to site-matched control skin from healthy volunteers. We demonstrate that relatively healthy-appearing perilesional skin (2cm away from the target nodule) has the same inflammatory profile as the visibly inflamed lesional skin (target nodule) and is marked by an increase of Th17 and neutrophil-related signatures. Given that inflammation in HS extends beyond visible nodules to perilesional skin, we asked if dermal inflammation also contributes to disease pathogenesis. Dermal tunnels, also known as tracts or sinuses, are structures unique to HS and have been considered an end-stage feature of the disease. By examining biopsies of dermal tunnels, we show that tunnels recapitulate features of the overlying epidermis and are associated with increased infiltration of T cells, dendritic cells and neutrophils, formation of neutrophil extracellular traps, and increased production of epithelium-derived inflammatory cytokines. Our work demonstrates that dermal tunnels are active contributors to the inflammatory burden of HS. To address whether tunnels are associated with a unique HS subtype, we assessed serum biomarkers in HS compared to healthy controls. Patients with tunnels had higher levels of IL-17 regulated neutrophil gelatinase-associated lipocalin (LCN2), and serum level of this biomarker correlated with clinical severity. These data demonstrate that HS tunnels are associated with a unique inflammatory profile in the skin and blood, suggesting a novel HS endotype. Data from our clinical trial of brodalumab, a human anti-IL-17 receptor A (IL-17RA) monoclonal antibody, provides the first molecular characterization of IL-17 pathway blockade in HS. We demonstrate that treatment with brodalumab reduces several pathogenic inflammatory axes in HS skin and serum. We also establish that perilesional skin provides a more robust assessment of treatment response. To further support HS stratification in the context of therapeutic antagonism, we demonstrate that patients with high expression of LCN2 in skin and IL-17A in serum had a superior molecular response in the skin as measured by a greater decrease of known inflammatory mediators of HS. Furthermore, we validate that dermal tunnels are therapeutically targetable, exhibiting decrease of tunnel wall and lumen diameter, as well as a decrease in clinical drainage. Taken together, this work provides novel insight into HS pathogenesis. Given the equally high inflammation present in lesional and perilesional HS skin, our data suggests there is a large field of inflammation beyond visible lesions. HS can be subdivided into unique subtypes, potentially introducing the concept of disease endotypes in this highly heterogeneous disease. This has direct applicability towards stratification of patients who may be better responders in the context of targeted therapy in HS.

Comments

A Thesis Presented to the Faculty of The Rockefeller University in Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy

Download

Included in

Life Sciences Commons

Share

COinS