Background

Apremilast is an effective treatment for Psoriatic Arthritis (PsA), despite its poorly elucidated effects on the immune system, especially on innate immune cells which play a relevant role in the pathogenesis of PsA.

 

Objectives

The objectives of this study were to define: (a) the ex vivo effects of apremilast on cytokine production by peripheral blood monocyte-derived macrophages, T cells, and innate-like lymphocytes in PsA patients, based on clinical response; (b) the role of serum IL-23 levels in predicting the clinical response to apremilast in PsA patients.  

 

Methods

Patients with PsA starting apremilast and patients with knee osteoarthritis (OA), as controls, were enrolled. Peripheral blood samples were obtained at baseline (BSL) from all subjects, and after one (T1M) and four months (T4M) in PsA cases. Monocytes were isolated and differentiated into M1-macrophages to assess gene expression (IL-23, TNF-α, and IL-1β by qPCR) and cytokine production (ELISA). Flow cytometry was used to assess the phenotype (T, γδT, NK, NKT-like, ILC1, ILC3, MAIT cells) and cytokine production (IFNγ, IL-17, IL-9) of lymphocytes. 

 

Results

Seventeen out of 23 patients with PsA (mean age 55±14 years; 10 females; median baseline DAPSA 16.3) showed a clinical response after 4 months of apremilast treatment. 

Baseline macrophage gene expression of IL-23 was significantly higher in PsA compared to OA and decreased after 4 months of treatment (Panel A1). Regarding clinical response, responders had higher baseline expression of IL-23 compared to non-responders; moreover, only in responders did IL-23 decrease after 4-month therapy (Panel A2). When testing serum levels of IL-23, a baseline concentration >1.4pg/mL predicted the response to apremilast at 4 months with moderate accuracy (AUCROC 0.79; sensitivity 100%, specificity 68%: Panels A3-4), while C-reactive protein, clinical features, or concurrent therapies did not show significant differences. 

Only in responder patients, apremilast reduced the expression of IL-17 from T cells (T1M, T4M; Panel B) and ILC3 (only T1M), IFNγ from γδT cells (T1M, T4M; Panel C1), and ILC1 (T1M), IL-9 from γδT cells (T1M, T4M; Panel C2).

 

Conclusions

Higher baseline serum levels of IL-23, possibly reflecting an IL-23 myeloid signature, identify PsA patients responding to apremilast. After 4 months, apremilast-responder patients showed a significant reduction in IL-23 expression by blood monocyte-derived M1 macrophages, and in IL-17, IL-9, and IFN-γ in T lymphocytes and γδT cells, respectively.

 

Figure. Summary of significant results concerning IL-23 expression from monocyte-derived macrophages and serum levels (Panel A), IL-17 production from conventional T cells (Panel B), and modulation of γδT cells by apremilast (Panel C).