AB0146 Apremilast potently inhibits il-12/il-23p40 production in human arthritic ex vivo models
Authors: T.W. Kragstrup, M. Adams, S. Lomholt, M. Nielsen, L. Heftdal, P. Schafer, B. Deleuran
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Apremilast (Otezla) is a phosphodiesterase 4 (PDE4) inhibitor approved for the treatment of psoriasis and psoriatic arthritis (PsA), but the reason why apremilast shows clinical effect in PsA is not fully understood. <h3>Objectives</h3> The objective of this study was to study the downstream effects of apremilast on cells of the inflamed joint in <i>ex vivo</i> models of immune mediated inflammatory arthritis. First, we tested the effect of apremilast on the secretion of several cytokines, chemokines and growth factors by synovial fluid mononuclear cells (SFMCs). Then, we tested whether apremilast affect factors involved in structural changes by studying fibroblast-like synovial cells (FLSs), osteoclasts, synovial macrophages, and osteoblasts. <h3>Methods</h3> Synovial fluid was obtained from a study population consisting of patients with active rheumatoid arthritis (RA), psoriatic arthritis (PsA) or peripheral spondyloarthritis (SpA) with at least one swollen joint (n=18). Synovial fluid mononuclear cells (SFMCs) cultured for 48 hours were used to study the effect of apremilast on secretion of a large panel of cytokines, chemokines and growth factors using the Olink Proseek Multiplex interferon I panel. These effects were compared with the effects of the tumour necrosis factor alpha (TNFα) inhibitor adalimumab. Further, fibroblast-like synovial cells (FLSs) were used to study metalloproteinase secretion, SFMCs cultured for 21 days were used to study inflammatory osteoclastogenesis and macrophage differentiation, an osteoclast pit formation assay was used to study osteoclast activity, and a mineralization assay was used to study new bone formation. <h3>Results</h3> In SFMCs cultured for 48 hours apremilast decreased the production of IL-12/IL-23p40 (the shared subunit of IL-12 and IL-23) (p&lt;0.00001), colony stimulating factor 1 (p=0.009), CD6 (p=0.03), CD40 (p=0.04), and MCP-1 (p=0.02), and increased the production of C-X-C motif chemokine 5 (p=0.003) dose-dependently. In sub-analyses, the apremilast induced decrease in cytokine production was greater in cultures with a high lymphocyte count and in cultures from patients with a low C-reactive protein level. Further, apremilast had a very different response signature compared with adalimumab, e.g. with a much greater inhibition of IL-12B (p=0.01) and less inhibition of IL-8 (p=0.0001) (see Figure). In SFMCs cultured for 21 days apremilast increased the secretion of IL-10 (p=0.04) and in FLS cultures apremilast decreased MMP3 production (p=0.005). Apremilast decreased osteoclast pit formation but did not change mineralization by human osteoblasts. <h3>Conclusions</h3> This study reveals the downstream effects of apremilast in <i>ex vivo</i> models of arthritis with a strong inhibition of IL-12/IL-23p40. Our findings could explain some of the efficacy of apremilast seen in IL-12/IL-23 driven immune mediated inflammatory diseases such as psoriasis and psoriatic arthritis. <h3>Disclosure of Interest</h3> T. Kragstrup: None declared, M. Adams: None declared, S. Lomholt: None declared, M. Nielsen: None declared, L. Heftdal: None declared, P. Schafer Shareholder of: Celgene, Employee of: Celgene, B. Deleuran: None declared