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. 2024 Dec 4:15:1455134.
doi: 10.3389/fimmu.2024.1455134. eCollection 2024.

Serum IL-23 levels reflect a myeloid inflammatory signature and predict the response to apremilast in patients with psoriatic arthritis

Maria De Santis  1   2 , Antonio Tonutti  1   2 , Natasa Isailovic  2 , Francesca Motta  1   2 , Radu Marian Rivara  2 , Rita Ragusa  2 , Giacomo M Guidelli  2 , Marta Caprioli  2 , Angela Ceribelli  1   2 , Daniela Renna  2 , Nicoletta Luciano  1   2 , Carlo Selmi  1   2
Affiliations

Serum IL-23 levels reflect a myeloid inflammatory signature and predict the response to apremilast in patients with psoriatic arthritis

Maria De Santis et al. Front Immunol. .

Abstract

Background: The phosphodiesterase 4 (PDE4) inhibitor apremilast downregulates the production of IL-23 and other pro-inflammatory cytokines involved in the pathogenesis of psoriatic arthritis (PsA).

Aim: To investigate the effects of apremilast on the production of cytokines by peripheral blood monocyte-derived macrophages, innate-like lymphocyte cells (ILCs), mucosal-associated invariant T (MAIT) cells, γδ T cells, natural killer (NK) cells, and NKT-like cells from patients with PsA manifesting different clinical responses to the treatment.

Methods: Peripheral blood samples were obtained from patients with PsA at baseline and after 1 and 4 months of apremilast therapy (n = 23) and 20 controls with osteoarthritis. Cytokine expression in peripheral blood monocyte-derived macrophages and ILCs/MAIT/γδT/NK/NKT-like cells was tested by RT-PCR and FACS analyses, respectively; cytokine levels in culture supernatants and sera were analyzed by ELISA.

Results: PsA monocyte-derived macrophages exhibited higher expressions of IL-23, IL-1β, and TNF-α, compared with OA controls, more profoundly in patients responding to apremilast. There were 17/23 (74%) PsA patients who were classified as responders to apremilast at 4 months, and a baseline serum IL-23 >1.4 pg/mL was associated with the responder status (AUCROC 0.79; sensitivity 100%, specificity 68%). Of note, apremilast led to a significantly reduced expression of IL-23 in peripheral blood monocyte-derived macrophages; IL-17 in ILC1 and in T cells of responder patients; IFN-γ in γδ T lymphocytes.

Conclusion: An enhanced myeloid inflammatory signature characterizes PsA monocyte-derived macrophages, and serum IL-23 levels represent candidate biomarkers for PsA response to apremilast.

Keywords: cytokines; immunology; innate lymphocyte; macrophages; precision medicine; spondyloarthritis (including psoriatic arthritis).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors received funding and consultation fees from Amgen.

Figures

Figure 1
Figure 1
Gene expression (reported as fold change) and supernatant levels (pg/mL) of inflammatory cytokines (IL-23, TNF-α, and IL-1β) from monocyte-derived M1 macrophages. Data are reported for OA controls and patients with PsA at the baseline condition (T0), after 7 days (T7D), 1 month (T1M), and 4 months (T4M) of treatment with apremilast. *p < 0.05 comparing OA controls and PsA patients at baseline.
Figure 2
Figure 2
Gene expression (reported as fold change) and supernatant levels (pg/mL) of inflammatory cytokines (IL-23, TNF-α, and IL-1β) from monocyte-derived M1 macrophages in patients responding and not responding to apremilast. Data are reported for the baseline condition (T0), after 7 days (T7D), 1 month (T1M), and 4 months (T4M) of treatment with apremilast. *p < 0.05 comparing responders vs. non-responders.
Figure 3
Figure 3
Comparison between baseline serum levels of IL-23 (pg/mL) between responders and non-responders to apremilast treatment (A). ROC curve for baseline serum IL-23, using the cutoff of 1.4 pg/mL (B).
Figure 4
Figure 4
Production of IL-17 from ILC1 (A) and T cells (B) at baseline (BSL), after one (T1M) and 4 months (T4M) of apremilast treatment in responders and non-responders. For Panel A: *p < 0.05 comparing baselines for responders vs. non-responders at T4M. **p < 0.05 comparing baseline and T1M. For Panel B: *p < 0.05 comparing baseline and T1M; **p < 0.05 comparing baseline and T4M.
Figure 5
Figure 5
Production of IFN-γ from γδ T cells at baseline (BSL) was higher in responders compared with non-responders (#p < 0.05) and significantly decreased after 4 months (T4M) of treatment with apremilast only in responders (**p < 0.05) (A). Production of IL-10 from NKT-like cells was higher in responders compared with non-responders at baseline (#p < 0.05) and at T4M (##p < 0.05) (B).
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