Original article Apremilast increases IL-10-producing regulatory B cells and decreases proinflammatory T cells and innate cells in psoriatic arthritis and psoriasis Athanasios Mavropoulos 1 , Efterpi Zafiriou 2 , Theodora Simopoulou 1 , Alexandros G. Brotis 3 , Christos Liaskos 1 , Aggeliki Roussaki-Schulze 2 , Christina G. Katsiari 1 , Dimitrios P. Bogdanos 1 and Lazaros I. Sakkas 1 Abstract Objectives. Psoriatic arthritis (PsA) and psoriasis are immune-mediated inflammatory diseases sharing common im- munological mechanisms. Regulatory B cells (Breg cells) producing IL10 (B10 cells), a critical anti-inflammatory B-cell subset, were found to be decreased in both PsA and psoriasis. Apremilast, a phosphodiesterase-4(PDE4) inhibitor, increases IL-10 and therefore, we examined the effect of apremilast on Breg cells. Methods. Fifty patients, including 20 with PsA and 30 with psoriasis, were included in the study. The effect of apre- milast on Breg cells at 3, 6 and 12 months post-treatment, was examined by flow cytometry in ODN2006 (TLR9)- stimulated peripheral blood mononuclear cells and magnetically-isolated cells. Th1 cells, Th17 cells and NKT were also measured. Results. Ex vivo stimulated cell analysis identified that post-apremilast (IL-10+CD19+) B10 cells were increased in all PsA and psoriasis patients and correlated with psoriatic skin and joint clinical improvement. Apremilast decreased IFNg(+) T and NKT cells and IL-17(+)NKT cells. B10 cells also inversely correlated with Th1 cells, and IFNg(+)NKT cells. Conclusion. These results suggest that Breg cells are a major target of apremilast in PsA and psoriasis and that apremilast-induced increase of Breg cells is associated with a decrease of Th1 cells, IFNg-producing NKT cells and IL- 17-producing NKT cells. Key words: spondylarthropathies, psoriatic arthritis, B-cells, cytokines, inflammatory mediators, inflammation, T cells Rheumatology key messages . We examined effects of apremilast on Bregs, Th1, Th17 and NKT cells in psoriatic disease. . Bregs increased in PsA and psoriasis patients during apremilast treatment and correlated with clinical response. . Bregs inversely correlated with Th1, IFNg + and IL-17+ NKT cells in PsA and psoriasis. Introduction PsA is an inflammatory joint disease in patients with psor- iasis, a common immune-mediated skin disease with a strong genetic component [1]. A recent meta-analysis study found that 20% of patients with psoriasis have PsA [2]. However, if enthesitis and dactylitis are included in the inflammatory arthritic manifestations, up to two- thirds of psoriasis patients develop PsA [3, 4]. This finding, along with common pro-inflammatory pathways (TNFa, IFNg and IL-23/IL-17) involved in both psoriasis and PsA, as well as T-cell clones shared between skin lesions and joints [57], led investigators to propose that psoriasis and PsA are one disease with different manifestations [1, 8]. In a previous study, we found that IL-10-producing regulatory B cells (Breg cells) were decreased in PsA and psoriasis and inversely correlated with Th1 and Th17 cells [9]. Breg cells are a subset of B cells with anti-inflammatory properties, as they inhibit pro-inflamma- tory T cells and maintain regulatory T cells preventing autoimmunity [10, 11]. Breg cells mediate their effects 1 Department of Rheumatology and Clinical Immunology, 2 Department of Dermatology and 3 Department of Neurosurgery, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa, Greece Correspondence to: Lazaros I. Sakkas, Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Larissa 41 110, Greece. E-mail: lsakkas@med.uth.gr Submitted 12 June 2018; accepted 30 March 2019 ! The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com RHEUMATOLOGY Rheumatology 2019;58:22402250 doi:10.1093/rheumatology/kez204 Advance Access publication 17 June 2019 CLINICAL SCIENCE Downloaded from https://academic.oup.com/rheumatology/article/58/12/2240/5519826 by guest on 08 March 2024