Higher Beta-Defensin 2 Levels Linked to Better Clinical Response to Secukinumab Treatment

In patients with psoriatic arthritis (PsA), beta-defensin 2 (BD-2) was associated with clinical response to treatment with secukinumab. Specifically, those with high levels of BD-2 at baseline were able to achieve and sustain higher rates of clinical response after treatment, according to a study published in Rheumatic and Musculoskeletal Diseases.¹

Enrico Ferrero, BSc, MSc, PhD

Credit: eMedEvents.com

Common clinical manifestations of the condition include tender and swollen joints, psoriasis activity on skin and nails, pain, fatigue, and impaired quality of life. Although several effective targeted therapies are currently available to treat this patient population, biomarkers predicting treatment response in PsA are currently lacking. Despite these advancements in care, 4 out of 10 patients with PsA have inadequate response to cytokine inhibitors and only 6 out of 10 patients achieve a 20% improvement in clinical endpoints.²

“In precision medicine, endotyping refers to the dissection of a disease (or multiple related diseases) into subtypes informed by underlying molecular mechanisms,” wrote Enrico Ferrero, BSc, MSc, PhD, Novartis Institutes for BioMedical Research, Basel, Switzerland, and colleagues. “When relating molecular read-outs to subsequent clinical response, prognostic biomarkers forecast clinical outcome regardless of intervention, whereas predictive biomarkers forecast clinical response to treatment. A recent literature review on predictive biomarkers in psoriasis and PsA highlighted the lack of independent validation of reported biomarkers in large cohorts.”

Investigators evaluated proteomics data taken from serum samples of 1989 patients with PsA from an array of placebo-controlled phase 3 clinical trials (FUTURE 1-5 and EXCEED) assessing secukinumab, an interleukin-17 inhibitor (IL-17). They also evaluated the phase 3 rheumatoid arthritis (RA) trials REASSURE, REASSURE 2, and NURTURE 1.

Statistical learning with controlled feature selection was used to uncover predictive biomarkers of clinical response. The top biomarker candidate was validated and evaluated separately in a trial of almost 800 patients with PsA treated with either secukinumab or adalimumab, a tumor necrosis factor inhibitor (TNF).

Serum levels of BD-2 at baseline were shown to be significantly linked with subsequent clinical response, as defined by the American College of Rheumatology (ACR) 20%, 50%, and 70% improvement rates (ACR20, ACR50, and ACR70, respectively). Investigators noted that these findings may be explained by the fact that TNF and IL-17 pathways are very similar.

Results were further confirmed in 2 independent clinical studies not used for discovery. Stability selection discovered 3 features linked to clinical response after 16 weeks of treatment. BD-2 was the only secukinumab-specific SOMAmer selected.

While BD-2 has been previously associated with psoriasis severity, the predictivity of BD-2 was independent of the baseline Psoriasis Area and Severity Index (PASI). Associations were determined as early as 4 weeks into treatment with secukinumab and were sustained up to 52 weeks. Further, BD-2 was also shown to predict response to adalimumab treatment. However, BD-2 levels did not predict response to secukinumab in a separate SomaScan analysis of 851 patients with RA. Inconclusive data were also observed in psoriasis cohorts, although this may be due in part to small sample sizes. In patients with PsA, investigators hypothesized there are certain patients with an increase in IL-17 pathway activity who are more likely to respond to IL-17 inhibitor treatment.

“These results suggest that there may be an IL-17–driven endotype of PsA with higher serum BD-2 levels and an elevated response rate to secukinumab, which raises the possibility for further precision medicine approaches for the significant remaining unmet medical need in PsA,” investigators concluded.

References

1. ^{Cardner M, Tuckwell D, Kostikova A, et al. Analysis of serum proteomics data identifies a quantitative association between beta-defensin 2 at baseline and clinical response to IL-17 blockade in psoriatic arthritis. RMD Open. 2023;9(2):e003042. doi:10.1136/rmdopen-2023-003042}
2. ^{Veale DJ, Fearon U. The pathogenesis of psoriatic arthritis. Lancet 2018;391:2273–84. doi:10.1016/S0140-6736(18)30830-4}