Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
Anti-Inflammatory Activity of Apremilast Against T Cells, Chondrocytes, and Rheumatoid Arthritis Synovial Fibroblasts in Vitro.
Capone, Lori, Rogovitz, Audry, Gandhi, Anita, Schafer, Peter
Background/Purpose:
Apremilast (APR) is a novel, orally available small molecule that specifically targets phosphodiesterase 4 (PDE4), thereby modulating multiple pro-inflammatory and anti-inflammatory mediators in both immune and non-immune cells. T cells secrete various cytokines and chemokines that play a role in RA and spondylarthritis. In addition, cytokines produced by chondrocytes and synoviocytes contribute to inflammatory joint diseases such as arthritis and in bone damage, and are increased in synovial fluid of spondylarthritis and RA patients.
Methods:
To explore the modulation of various cellular responses involved in arthritis and joint damage, the effect of APR on inflammatory responses of primary human T cells, chondrocytes, and RA patient synovial fibroblasts was examined, and compared with that of other anti-rheumatic agents etanercept (ETAN), cyclosporine A (CsA), methotrexate (MTX), and prednisolone (PRED). Human peripheral blood total T cells from healthy donors were stimulated with anti-CD3 antibody. Total peripheral blood mononuclear cells were stimulated with Staphylococcal Enterotoxin B. Cytokine and chemokine protein levels were analyzed by cytometric bead array. Normal primary human chondrocytes and RA synovial fibroblasts were stimulated with IL-1b, IL-6 and IL-6R. IL-7 mRNA was measured by qRT-PCR.
Results:
In T cells, APR inhibited production of all T cell cytokines and chemokines measured (IL-2, IL-4, IL-13, IFN-gamma, TNF-alpha, CXCL10, CCL3, and CCL4) with 50% inhibitory concentrations (IC50s) of 15–360 ng/mL. CsA also inhibited all analytes, with IC50s of 4.7–140 ng/mL. In contrast, ETAN potently inhibited TNF-alpha (IC50=1.5 ng/mL), and to a lesser degree IL-13 and IP-10 (16–62 ng/mL), but IC50s for all other analytes were >1600 ng/mL. Notably, ETAN and CsA inhibited TNF-a by 90–95%, while APR inhibited TNF-a by a maximum of 70%. In chondrocytes, APR significantly inhibited IL-7 gene expression (IC50=140 ng/mL) to a greater degree than ETAN or MTX, while IL-7 inhibition by PRED was greatest. APR showed a trend of inhibition of avb3 integrin, ICAM-1 expression, and production of IL-8, MMP-3, and MMP-13 by chondrocytes. In stimulated RA synovial fibroblasts, APR inhibited IL-7 gene expression (IC50=1800 ng/mL), while PRED, MTX, and ETAN had no significant effect.
Conclusion:
Treatment of human T cells with APR resulted in inhibition of IL-2, IL-4, IL-13, IFN-gamma, TNF-alpha, CXCL10, CCL3, and CCL4, with a predominant pattern of partial inhibition. In chondrocytes and RA synovial fibroblasts, APR inhibited IL-7 gene expression. These results illustrate the distinct pattern of modulation of inflammatory responses by PDE4 inhibition, compared to other classes of drugs.
To cite this abstract, please use the following information:
Capone, Lori, Rogovitz, Audry, Gandhi, Anita, Schafer, Peter; Anti-Inflammatory Activity of Apremilast Against T Cells, Chondrocytes, and Rheumatoid Arthritis Synovial Fibroblasts in Vitro. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1844
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