Background: Apremilast, a phosphodiesterase-4 inhibitor, is approved for treating psoriatic arthritis (PsA) but its mechanisms of action remain elusive. Conventional T cells and innate lymphocytes, including NK cells, NKT cells, γδT cells, innate lymphoid cells (ILCs), and mucosal-associated invariant T (MAIT) cells play a pivotal role in PsA pathogenesis, contributing to IL-23-dependent and -independent pathways to IL-17 expression.

Objectives: To investigate the ex vivo effects of apremilast in PsA patients by characterizing: 1. the conventional T and innate lymphocytes (NK, NKT-like, γδT, ILC1/2/3, and MAIT); 2. The production of IL-17 by T cells, ILCs, and MAIT cells; 3. The production of IFN-γ, IL-9, and IL-10 from T cells, NK cells, NKT-like cells, γδT cells, and ILCs.

Methods: Peripheral blood samples were collected from 7 treatment-naïve patients with peripheral PsA (median age 48 years, IQR 44-58; 2 females; median DAPSA 15, IQR 10-18) prior to and 4 months after being treated with apremilast 30mg BID, and 5 knee osteoarthritis (OA) controls (median age 61, IQR 48-74; 2 females). Lymphocyte phenotype and cytokine production were analyzed by flow cytometry using unstimulated or stimulated conditions (PMA 50 ng/mL + ionomycin 1 μg/mL together with BFA) at baseline in both OA and PsA patients, and after 4 months of apremilast in PsA.

Results: At baseline, PsA patients had higher percentages of IFN-γ+ γδT cells, IL-9+ NK cells, and IL-10+ NKT-like, NK, and γδT cells compared to OA ( Figure 1, panels a-c ). Baseline IL-17 expression was similar between PsA and OA cells. After 4 months of apremilast therapy, all patients achieved low disease activity and a significant reduction in IFN-γ+ γδT cells, in IL-17+ conventional T cells, and in IL-17+ ILC1 cells was observed ( Figure 2, panels a-c ). Apremilast also led to a reduction in IL-10+ NK, NKT-like, and γδT lymphocytes ( Figure 2, panel d ). No significant effects in terms of cytokine production were induced on MAIT cells after apremilast treatment.

Conclusion: In responder PsA patients, apremilast down-modulates IFN-γ production mainly from innate-like cells, particularly γδT cells, whereas IL-17 production is inhibited also in conventional T cells. An IL-10 signature characterizes innate-like cells from patients with active PsA, and is down-regulated by apremilast, thus likely representing a counter-regulatory mechanism of the immune system towards dysregulated inflammation.

REFERENCES: NIL.

Figure 1.

IFN-γ, IL-9, and IL-10 expressing cells in psoriatic arthritis (PsA) patients before apremilast use and in osteoarthritis (OA) controls.

Figure 2.

Effect of apremilast on selected cytokines by different lymphocyte subsets from patients with PsA.

Acknowledgements: NIL.

Disclosure of Interests: Maria De Santis: None declared, Antonio Tonutti: None declared, Francesca Motta: None declared, Natasa Isailovic: None declared, Angela Ceribelli: None declared, Giacomo Maria Guidelli AbbVie, BMS, Eli-Lilly, Galapagos, Janssen, Novartis, AbbVie, BMS, Eli-Lilly, Galapagos, Janssen, Novartis, Marta Caprioli: None declared, Daniela Renna Janssen, Nicoletta Luciano AbbVie, BMS, Eli-Lilly, Galapagos, Janssen, AbbVie, BMS, Eli-Lilly, Galapagos, Janssen, Carlo Selmi AbbVie, Amgen, Alfa-Sigma, Biogen, Eli-Lilly, EUSA Pharma - Recordati, Galapagos, Janssen, Novartis, Octapharma, Pfizer, Recordati Rare Disease, SOBI, AbbVie, Amgen, Alfa-Sigma, Biogen, Eli-Lilly, EUSA Pharma - Recordati, Galapagos, Janssen, Novartis, Octapharma, Pfizer, Recordati Rare Disease, SOBI, AbbVie, Amgen, Janssen, Novartis, Pfizer.