TOPLINE:
Obesity was linked to reduced long-term effectiveness of biologic therapy in patients with severe plaque psoriasis in a study, with dysregulated innate immune responses contributing to treatment resistance.
METHODOLOGY:
- A cross-sectional study of 87 patients (mean age, 42.2 years; 24 women) with plaque-type severe psoriasis who went to the dermatology clinic at Gachon University Gil Medical Center, Incheon, South Korea, between January 2012 and December 2022.
- Participants had Psoriasis Area and Severity Index (PASI) scores > 10 and body surface area scores > 10 despite conventional treatment for > 3 months and received biologics for at least 24 months. Treatment resistance was defined as failure to maintain a 75% improvement in PASI score and switching biologics because of reduced efficacy within 24 months.
- Spatial transcriptomics (ST) was performed on lesional skin biopsies from six biologic-naive patients with obesity (body mass index [BMI], ≥ 25), later categorized by response to therapy. Gene expression profiles were analyzed using multimodal integration with public single-cell RNA-seq data, KEGG pathway enrichment, and ligand-receptor/ligand-target analyses.
- The mean duration of treatment with the first biologics was 16.06 months, and the median PASI score at the first switch was 7.8.
TAKEAWAY:
- Overall, 16 (18.4%) patients switched to other biologics because of an early loss of therapeutic efficacy. Obesity (BMI ≥ 25) was the only clinical factor independently associated with biologic resistance (OR, 17.3; P = .009).
- In the ST analysis, epidermal clusters 2, 3, and 8 and dermal inflammatory cluster 5 showed the highest transcriptional activity. Enriched pathways in resistant lesions included interleukin (IL)-17 and IL-36 signaling, Th1/Th2 differentiation, and toll-like receptor pathways.
- Key overexpressed genes in resistant lesions included TNFSF10, CXCL8, LCN2, S100A8, and S100A9, particularly in the epidermis. Ligand-receptor analyses indicated heightened IL-1, IL-36, and tumor necrosis factor (TNF) signaling across epidermal and dermal layers.
- Immunostaining confirmed higher protein expression of lipocalin 2, S100A8/S100A9, IL-36 isoforms, IL-1RA, TRAIL, and TNF-alpha in treatment-resistant lesions. CD11b-positive innate myeloid cells were significantly increased in the resistant group, suggesting a role of an overactive innate immune system in reducing the long-term effectiveness of biologic therapies.
IN PRACTICE:
“These multimodal integrative data on gene expression and pathogenic features collectively underscore the role of imbalanced epidermal innate immune responses in early resistance to biologic therapy in patients with obesity with severe psoriasis, with neutrophils emerging as a key mediator in the process,” the authors wrote. “Given that current biologics primarily target dermal adaptive immune mediators such as IL-17, IL-22, and IL-23, there is a need to develop novel therapeutic strategies that address epidermal innate immune responses, including neutrophils,” they added.
SOURCE:
The study was led by Hee Joo Kim, MD, PhD, Department of Dermatology, Gil Medical Center, Gachon University College of Medicine, and was published online on April 2 in JAMA Dermatology.
LIMITATIONS:
Study limitations included the cross-sectional design and small sample size, and the study was performed at a single center. Findings may not be generalizable to non-Asian ethnic groups.
DISCLOSURES:
The study was supported by the National Research Foundation of Korea, the Korean government, and Gachon University.
This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.