Real-World Clinical Experience With the IL-17 Receptor A Antagonist Brodalumab

February 2020 | Volume 19 | Issue 2 | Original Article | 132 | Copyright © February 2020


Published online January 17, 2020

Miriam S. Bettencourt

Bettencourt Skin Center/Advanced Dermatology & Cosmetic Surgery, Henderson, NV; University of Nevada, Las Vegas, NV

Abstract
Psoriasis is a chronic, inflammatory, remitting/relapsing autoimmune dermatologic condition that manifests with scaly, erythematous plaques. It has a significantly negative effect on patient quality of life, as well as increasing their risk of numerous comorbid diseases. Patients are typically treated initially with topical steroids, retinoids, and vitamin D derivatives followed by phototherapy and systemic treatments, including oral, subcutaneous or intravenous immunomodulatory drugs, if needed.

Psoriasis is driven by T-cell activation and associated with the secretion of proinflammatory cytokines and a dysregulated interleukin- 23/T helper 17 (Th-17) inflammatory response. Eleven biologic therapies and 6 biosimilars that target the 3 main immunological pathways— tumor necrosis factor-α (TNF-α), interleukin 23 (IL-23), and IL-17, are approved for the treatment of plaque psoriasis. While most demonstrate similar effectiveness in clinical trials, patient response in real-world settings is varied. Thus, it is important that the clinician understand the mechanism of action of these drugs as well as their safety profile, unique benefits, and limitations. They must also consider the patient’s disease presentation, severity, and comorbid conditions when determining the most appropriate therapy.

This article focuses on the IL-17 inhibitors, secukinumab, ixekizumab, and brodalumab, highlighting their unique mechanisms of action and their efficacy and safety in a real-world clinical setting.

J Drugs Dermatol. 2020;19(2)132-136 doi:10.36849/JDD.2020.4774

INTRODUCTION

Psoriasis is a chronic, inflammatory, remitting/relapsing autoimmune dermatological condition characterized by scaly, erythematous plaques. Patients with psoriasis experience a significantly reduced quality of life due to discomfort from the physical symptoms as well as disability and disfigurement. They also have a higher risk of comorbid conditions, including psoriatic arthritis (PsA), cardiovascular disease, inflammatory bowel disease, metabolic syndrome, chronic kidney disease, mood disorders, including depression, and malignancy.1

While the etiology of psoriasis is unknown, there have been many recent advances in the understanding of its pathogenesis. We now know that psoriasis is a T-cell mediated disease involving a dysregulated inflammatory response of the interleukin (IL) 23/T-helper (Th)-17 pathway. In this process, IL- 23 is overproduced by dendritic cells and keratinocytes, which stimulates Th17 cells within the dermis to produce and release additional inflammatory cytokines. This, in turn, activates an inflammatory cascade of downstream effector molecules including IL-17A, IL-17F, IL-22, IL-21, and tumor necrosis factor-α (TNF-α), which is responsible for the keratinocyte hyperproliferation that results in the characteristic scaly plaques.2-4 Studies conducted in mice demonstrate that removing either IL-23 or IL-17 decreases the progression of psoriasis.5,6 Mice injected with monoclonal antibodies targeting IL-17 blocked, or neutralized, downstream signaling of this cytokine and decreased epidermal hyperplasia.5

Similarly, genetically modifying mice to not express IL- 23 or IL-17 receptors significantly reduced psoriatic lesion development upon stimulation with the lesion-causing tumor promoter 12-O-tetradecanoylphorbol-13-acetate.7 This greater understanding of the immune-mediated pathology of the disease has led to the development of monoclonal antibodies and fusion proteins that block specific cytokines or cytokine receptors involved in psoriatic inflammation.

Currently available biologics are the TNF-α inhibitors infliximab, adalimumab, certolizumab, and etanercept; the IL-12/13 inhibitor ustekinumab; the IL-17 inhibitors secukinumab and ixekizumab; the IL-17 receptor blocker brodalumab; and the IL-23 inhibitors guselkumab, tildrakizumab, and risankizumabrzaa.1 Biosimilars to infliximab, adalimumab, and etanercept are also available.