Association of Obesity and Innate Immune Markers With Resistance to Biologic Therapy in Psoriasis

Importance: Currently available biologics specifically target dermal adaptive immune molecules, such as interleukin (IL)-17 and IL-23, which are crucial in the pathogenesis of psoriasis. Despite their remarkably enhanced therapeutic effects compared with those of traditional anti-inflammatory systemic medications, 25% to 50% of patients are still resistant to biologic therapy. Objective: To delineate the inflammatory microenvironmental factors that affect sustained treatment response in patients with severe psoriasis. Design, Setting, and Participants: A cross-sectional study was carried out including patients aged 18 years or older who visited the Gachon University Gil Medical Center dermatology clinic between January 2012 and December 2022 with plaque-type severe psoriasis with a Psoriasis Area and Severity Index score greater than 10 and body surface area larger than 10 despite conventional treatment with cyclosporine, methotrexate, acitretin, and phototherapy for longer than 3 months, and treatment with biologics for at least 24 months. Analysis was carried out from December 2023 to September 2024. Main Outcome and Measure: Clinical and inflammatory factors associated with sustained response to biologics therapy. Results: Among the 87 patients (mean [SD] age, 42.2 [12.5] years; 24 female patients and 63 male patients) included in the study, 16 (18.4%) had to switch to other biologics because of an early loss of therapeutic efficacy. Having overweight (body mass index, >25) was the only clinically relevant factor (odds ratio, 17.3; 95% CI, 3.2-434.6; P = .009). Other factors, including initial disease severity before biologics or disease duration until the first use of biologics, were not different between patients with treatment-resistant disease and those with a sustained treatment response. Spatial transcriptomics pathway analyses revealed enriched innate immune signaling and T-helper 17 cells (Th17)/IL-17 signaling pathways, with upregulated expression of innate immune- or neutrophil-related genes, such as TNFSF10, CXCL8, LCN2, S100A8, and S100A9, mainly in the epidermis. Enriched ligand-receptor interactions were observed in the IL-36 family of cytokines, antimicrobial peptides, and tumor necrosis factor (TNF) signaling. Immunofluorescence analysis showed enhanced protein expression of lipocalin 2, S100A8/A9, IL-36α, IL-36γ, IL-1RA, and TNF-related apoptosis-inducing ligand (TRAIL) in the epidermis. Conclusions and Relevance: This cross-sectional study found that dysregulated innate immune responses in the epidermis and heightened neutrophil activity may be responsible for decreased sustainability of therapeutic responses to biologics. Given that current biologics mainly target dermal adaptive immune-related mediators, the development of novel therapeutic strategies to target the epidermal innate immune response, including neutrophils, is warranted.