INTRODUCTION
Psoriasis is a chronic immune-mediated inflammatory disease driven by dysregulated interleukin-17 (IL-17) signaling across skin and musculoskeletal tissues. While upstream IL-23 inhibition and selective IL-17 cytokine blockade have improved outcomes, IL-17 cytokines can arise from IL-23-independent pathways and nonclassical cellular sources, sustaining inflammation despite ligand-specific inhibition and highlighting IL-17 receptor A (IL-17RA) as a central therapeutic target. This review examines clinical trial and realworld evidence for brodalumab, an IL-17RA antagonist, with a focus on efficacy, durability, safety, and its clinical positioning across the spectrum of psoriatic disease.
Role of IL-17 in Plaque Psoriasis and Psoriatic Arthritis: Focus on IL-17 Receptor
The IL-17 cytokine family comprises six structurally related isoforms -- IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F -- that collectively contribute to inflammatory signaling in psoriasis and psoriatic arthritis (PsA).1 These cytokines are produced by both immune and nonimmune cell populations and signal through heterodimeric receptor complexes that share the IL-17 receptor A (IL-17RA) subunit, creating a central convergence point for downstream inflammatory pathways. In psoriatic disease, IL-17-mediated signaling drives keratinocyte activation, epidermal hyperplasia, neutrophil recruitment, and persistent inflammation across skin and musculoskeletal compartments.2
Although IL-23 is a key regulator of Th17 differentiation, IL-17 cytokines can be generated through IL-23-independent pathways, reflecting heterogeneous mechanisms of immune activation.3 Classical Th17 cells retain the capacity to produce IL-17 in response to alternative inflammatory cues, while innate-like immune populations -- including γδ T cells, innate lymphoid cells, mast cells, and neutrophils -- are enriched in psoriatic skin and synovium and can rapidly release IL-17 independently of IL-23. Histologic analyses further demonstrate that mast cells and neutrophils constitute major sources of IL-17 in lesional skin, whereas IL-17-positive T lymphocytes are relatively sparse, underscoring the importance of nonclassical IL-17-producing cells in tissue-level disease persistence.4,5
Transcriptomic studies provide strong support for the clinical relevance of these IL-23-independent pathways. Following IL-17RA blockade, lesional skin demonstrates rapid and broad normalization of the psoriatic transcriptome, with suppression of thousands of aberrantly expressed genes within weeks of treatment.6 IL-17RA inhibition results in coordinated downregulation of multiple IL-17 ligands, including IL-17A, IL-17F, and IL-17C, and robust suppression of keratinocyte-driven inflammatory gene programs that are not fully normalized by IL-23 inhibition alone.7,8
Role of IL-17 in Plaque Psoriasis and Psoriatic Arthritis: Focus on IL-17 Receptor
The IL-17 cytokine family comprises six structurally related isoforms -- IL-17A, IL-17B, IL-17C, IL-17D, IL-17E (IL-25), and IL-17F -- that collectively contribute to inflammatory signaling in psoriasis and psoriatic arthritis (PsA).1 These cytokines are produced by both immune and nonimmune cell populations and signal through heterodimeric receptor complexes that share the IL-17 receptor A (IL-17RA) subunit, creating a central convergence point for downstream inflammatory pathways. In psoriatic disease, IL-17-mediated signaling drives keratinocyte activation, epidermal hyperplasia, neutrophil recruitment, and persistent inflammation across skin and musculoskeletal compartments.2
Although IL-23 is a key regulator of Th17 differentiation, IL-17 cytokines can be generated through IL-23-independent pathways, reflecting heterogeneous mechanisms of immune activation.3 Classical Th17 cells retain the capacity to produce IL-17 in response to alternative inflammatory cues, while innate-like immune populations -- including γδ T cells, innate lymphoid cells, mast cells, and neutrophils -- are enriched in psoriatic skin and synovium and can rapidly release IL-17 independently of IL-23. Histologic analyses further demonstrate that mast cells and neutrophils constitute major sources of IL-17 in lesional skin, whereas IL-17-positive T lymphocytes are relatively sparse, underscoring the importance of nonclassical IL-17-producing cells in tissue-level disease persistence.4,5
Transcriptomic studies provide strong support for the clinical relevance of these IL-23-independent pathways. Following IL-17RA blockade, lesional skin demonstrates rapid and broad normalization of the psoriatic transcriptome, with suppression of thousands of aberrantly expressed genes within weeks of treatment.6 IL-17RA inhibition results in coordinated downregulation of multiple IL-17 ligands, including IL-17A, IL-17F, and IL-17C, and robust suppression of keratinocyte-driven inflammatory gene programs that are not fully normalized by IL-23 inhibition alone.7,8
