<scp>Interleukin‐17RA</scp> blockade by brodalumab decreases inflammatory pathways in hidradenitis suppurativa skin and serum
Authors: Kristina Navrazhina, John W. Frew, David Grand, Samuel C. Williams, Hong Hur, Juana Gonzalez, Sandra Garcet, James G. Krueger
Journal: British Journal of Dermatology (2022)

Background Hidradenitis suppurativa (HS) is an inflammatory skin disease with dysregulation of the interleukin (IL)-17 axis. Recently, we reported the clinical benefit of brodalumab, a human anti-IL-17 receptor A (IL-17RA) monoclonal antibody, in moderate-to-severe HS. Objectives To characterize the molecular response to brodalumab in HS skin and serum, and to identify biomarkers of treatment response. Methods Ten participants, who received brodalumab 210 mg /1·5 mL subcutaneously at weeks 0, 1, 2, 4 and every 2 weeks thereafter, were included in this molecular profiling study (NCT03960268). RNA sequencing and immunohistochemistry of nonlesional, perilesional and lesional HS skin biopsies, and Olink high-throughput proteomics of serum at baseline, weeks 4 and 12 were assessed. Results At week 12, brodalumab led to a decrease of overall inflammation, and improvement of psoriasis-, keratinocyte- and neutrophil-related pathways. Despite perilesional and lesional skin exhibiting no differentially expressed genes at baseline, treatment response was best assessed in perilesional skin. In serum, brodalumab treatment decreased pathways involved in neutrophil inflammation. Patients with higher baseline expression of neutrophil-associated lipocalin-2 (LCN2) in the skin or IL-17A in the serum demonstrated greater decreases of HS-related inflammatory cytokines as measured in skin biopsies at week 12. Conclusions IL-17RA inhibition by brodalumab decreases several pathogenic inflammatory axes in HS. Perilesional skin provides a valid and robust assessment of treatment response. Expression of LCN2 in skin or IL-17A in serum may be used as biomarkers to stratify patients that may have a superior molecular response to brodalumab. What is already known about this topic? Hidradenitis suppurativa (HS) is a chronic inflammatory disease with upregulation of several pro-inflammatory and keratinocyte proliferation-related pathways. Interleukin (IL)-17 is a known modulator of these pathways and has been implicated in the pathogenesis of HS. We have recently reported a clinical improvement in HS with brodalumab, an IL-17RA antagonist. What does this study add? This study details the molecular response to brodalumab using RNA sequencing, high-throughput proteomics and immunohistochemistry. This research identifies lipocalin-2 (LCN2) in skin and IL-17A in serum as potential predictive biomarkers for treatment response. These data may help guide physicians in choosing the appropriate therapy for patients with moderate-to-severe HS. What is the translational message? IL-17RA blockade with brodalumab is an effective treatment for patients with moderate-to-severe HS. Assessing pathways that respond to treatment, rather than individual biomarkers, may be a superior approach for molecular characterization of the treatment response in HS therapeutic studies. Brodalumab modulates neutrophil-related pathways in the skin and blood, and known psoriasis pathways in the skin. We demonstrate that patients with high baseline expression of IL-17-regulated neutrophil-created LCN2 in the skin or IL-17A in the serum have a superior molecular response to treatment, allowing the possibility for physicians to select therapeutic treatment based on baseline molecular profiles.