Novel systemic drugs for psoriasis: Mechanism of action for apremilast, a specific inhibitor of PDE4

To the Editor: The article, "Novel systemic drugs under investigation for the treatment of psoriasis,"1Gudjonsson J.E. Johnston A. Ellis C.N. Novel systemic drugs under investigation for the treatment of psoriasis.J Am Acad Dermatol. 2012; 67: 139-147Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar provides a valuable overview of investigational treatments for patients with psoriasis. However, the description of apremilast's mechanism of action is too narrow. Apremilast should not be considered only a T-cell inhibitor, as is indicated in Table I and Fig 2 of the original article. While it is accurate that inhibition of phosphodiesterase 4 (PDE4) by apremilast affects T-cell production of inflammatory cytokines, recent data on apremilast's mechanism of action illustrate additional effects in psoriasis. PDE4 is the predominant phosphodiesterase involved in the control of activity in inflammatory cells,2Salari P. Abdollahi M. Phosphodiesterase inhibitors in inflammatory bowel disease.Expert Opin Investig Drugs. 2012; 21: 261-264Crossref PubMed Scopus (34) Google Scholar yet it is also expressed in structural cell types involved in psoriasis, such as keratinocytes.3Schafer PH. Targeting PDE4 with apremilast, an orally available specific PDE4 inhibitor, in clinical trials for the treatment of psoriasis and arthritis. Presented at the International Congress on Autoimmunity; May 9-13, 2012; Granada, Spain.Google Scholar Indeed, in a study comparing psoriasis skin samples with normal skin samples, immunohistochemistry demonstrated that PDE4A, PDE4B, and PDE4D expression can be detected in inflammatory cells as well as in the structural and adnexal tissues of the skin.3Schafer PH. Targeting PDE4 with apremilast, an orally available specific PDE4 inhibitor, in clinical trials for the treatment of psoriasis and arthritis. Presented at the International Congress on Autoimmunity; May 9-13, 2012; Granada, Spain.Google Scholar Through inhibition of PDE4, apremilast causes an elevation of cyclic adenosine monophosphate, a naturally occurring intracellular secondary messenger that functions as a modulator of inflammatory responses,4Serezani C.H. Ballinger M.N. Aronoff D.M. Peters-Golden M. Cyclic AMP: master regulator of innate immune cell function.Am J Respir Cell Mol Biol. 2008; 39: 127-132Crossref PubMed Scopus (286) Google Scholar, 5Tasken K. Aandahl E.M. Localized effects of cAMP mediated by distinct routes of protein kinase A.Physiol Rev. 2004; 84: 137-167Crossref PubMed Scopus (628) Google Scholar thereby decreasing production of proinflammatory mediators, such as tumor necrosis factor (TNF)-α, interleukin (IL)-23, and interferon gamma, and increasing production of anti-inflammatory mediators, such as IL-10.6Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis.Biochem Pharmacol. 2012; 83: 1583-1590Crossref PubMed Scopus (301) Google Scholar The modulatory effects of apremilast on inflammatory activity have been demonstrated in multiple in vivo and in vitro models and studies in humans. In addition, apremilast has been shown to decrease proinflammatory cytokine production induced by toll-like receptor 4 agonism in peripheral blood mononuclear cells, T-cell receptor agonism, cytokine and immunoglobulin receptor agonism on natural killer cells, and ultraviolet light exposure of keratinocytes.7Schafer P.H. Parton A. Gandhi A.K. Capone L. Adams M. Wu L. et al.Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis.Br J Pharmacol. 2010; 159: 842-855Crossref PubMed Scopus (313) Google Scholar In lipopolysaccharide-stimulated peripheral blood mononuclear cells, apremilast reduced the production of TNF-α, interferon gamma, IL-12, and IL-23 and increased the production of IL-10.8Schafer PH. Effects of apremilast on innate and adaptive immune responses [poster]. Presented at: Annual Meeting of the European Society for Dermatological Research; September 7-12, 2011; Barcelona, Spain.Google Scholar In subjects with severe plaque psoriasis, apremilast reduced both infiltration of myeloid dendritic cells into the dermis and epidermis and inducible macrophage-type nitric oxide synthase mRNA expression,9Gottlieb A.B. Strober B. Krueger J.G. Rohane P. Zeldis J.B. Hu C.C. et al.An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast.Curr Med Res Opin. 2008; 24: 1529-1538Crossref PubMed Scopus (110) Google Scholar and in subjects with rheumatoid arthritis, apremilast reduced IL-7 gene expression in synovial fibroblasts.10Capone L, Rogovitz A, Gandhi AK, Schafer PH. Anti-inflammatory activity of apremilast against T cells, chondrocytes, and rheumatoid arthritis synovial fibroblasts in vitro [abstract 1844]. Presented at: Annual Scientific Meeting of the American College of Rheumatology; November 4-9, 2011; Chicago, IL.Google Scholar Based on available data, it is most appropriate to classify apremilast as a specific inhibitor of PDE4, which affects inflammatory signals across several cell types, thereby modulating the production of multiple cytokines and exerting influence on a number of physiologic aspects of psoriasis. Novel systemic drugs under investigation for the treatment of psoriasisJournal of the American Academy of DermatologyVol. 67Issue 1PreviewIn the last few years, there has been progress in identifying some of the risk genes for psoriasis. This has resulted in a major impetus toward drug development as many of the same pathways and processes identified in psoriasis have been shown to have major roles in other chronic inflammatory diseases, suggesting that psoriasis can be used as a treatment model for many other diseases. This has resulted in a shift in research toward a select number of biological processes and has been accompanied by a surge in drug development with over 20 systemic agents currently in clinical testing for psoriasis, many of which target the pathways identified through genetic and basic research. Full-Text PDF