Reduced Efficacy of Biological Drugs in Psoriatic Patients with HLA-A Bw4-80I KIR Ligands

Background: Biological drugs (biologics) are a highly effective therapy for the moderate to severe form of psoriasis, an immune-mediated dermatosis with a strong immunogenetic component. The interaction between human leukocyte antigen (HLA) class I ligands and killer immunoglobulin-like receptors (KIR) has a functional significance in the education of natural killer (NK) cells, and can thus influence the response to biologics. Objective: In this study, we investigated the impact of HLA-A and -B KIR ligands in the response to biologics in a cohort of psoriatic patients. Methods: Eighty-five patients with moderate to severe psoriasis treated with biologics (adalimumab, etanercept, infliximab, ustekinumab and secukinumab) were enrolled in the study. Clinical response was evaluated as patients attaining 50%, 75% or 90% reduction in the Psoriasis Area and Severity Index (PASI) (PASI 50, 75 or 90, respectively) over 6 months’ follow-up. Poor response was defined as PASI 50, and in this case patients shifted to treatment with a different biologic. Fifty-two patients (61.2%) showed excellent response (PASI 90) to the first biologic, while 33 patients (38.8%), needed two or more biologics before reaching an excellent response (PASI 90) and were considered difficult to treat. Results: Only HLA-A Bw4-80I ligands were associated with the response to biologics; in particular, they were linked with reduced response both at univariable analysis (odds ratio [OR] 3.11, 95% confidence interval [CI] 1.19–8.07; p = 0.019) and multivariable analysis (OR 5.02, 95% CI 1.40–17.97; p = 0.013). Conclusion: We suggest that the HLA-A Bw4-80I epitope could be a marker of reduced responsiveness to biologics. The possible reason for this is an increase of tumour necrosis factor (TNF)-α and the silencing of NK cells through the predominant interaction with the KIR3DL/S pair. HLA-KIR affinities might lead to a more efficient way to prescribe biologics.