Obesity and Epidermal Innate Immunity Linked to Resistance to Biologic Therapy in Psoriasis
Key Takeaways
Overweight psoriasis patients had a 17-fold higher risk of resistance to biologic therapy.
Innate immune dysregulation and neutrophilic inflammation in the epidermis may undermine biologic efficacy.
Current biologics may need to be complemented by therapies targeting epidermal innate pathways, researchers noted.
Patients with severe plaque psoriasis who are overweight are more likely to experience resistance to biologic therapies, according to new findings
The study researchers designed and conducted a cross-sectional study at Gachon University Gil Medical Center over a 10-year period, focusing specifically on the inflammatory drivers of sustained biologic treatment response in patients with severe plaque-type psoriasis (N=87). Despite long-term use of targeted IL-17 and IL-23 inhibitors, 18.4% of patients required switches in therapy due to early loss of efficacy, the authors reported.
The only clinical factor independently associated with treatment resistance was overweight status (BMI >25), which was linked to a striking 17-fold increased risk of biologic failure (OR = 17.3; 95% CI, 3.2 to 434.6; P = 0.009). Neither baseline disease severity nor duration of psoriasis prior to biologic initiation appeared to influence outcomes.
According to molecular analyses, patients who failed biologic therapy showed distinct inflammatory signatures in the epidermis. Spatial transcriptomics showed an upregulation of innate immune and neutrophil-related pathways—including Th17/IL-17 signaling—and overexpression of other genes (such as TNFSF10, CXCL8, LCN2, S100A8, and S100A9). IL-36 cytokines and TNF signalin were shown to have involvement in enriched ligand-receptor interactions. Elevated epidermal expression of TRAIL, lipocalin 2, and S100 proteins was confirmed via immunofluorescence.
“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,” the authors concluded.
Source: Kim Hyojin, et al. JAMA Dermatology. 2025. Doi:10.1001/jamadermatol.2025.0288