Mechanisms Underlying the Clinical Effects of Apremilast for Psoriasis openaccess articles

August 2018 | Volume 17 | Issue 8 | Original Article | 835 | Copyright © 2018

Carlo Pincelli MD,a Peter H. Schafer PhD,b Lars E. French MD,c Matthias Augustin MD,d James G. Krueger MD PhDe

aLaboratory of Cutaneous Biology, Department of Surgical, Medical, Dental and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy bDepartment of Translational Development, Celgene Corporation, Summit, NJ cDepartment of Dermatology, Zurich University Hospital, Zurich, Switzerland dInstitute and German Center for Health Services Research in Dermatology, University Medical Center of Hamburg, Hamburg, Germany eLaboratory of Investigative Dermatology, The Rockefeller University, New York, NY

Abstract

Psoriasis is a chronic, systemic, inflammatory disease with manifestations resulting from a dysregulated immune response. In psoriatic skin, expression of all phosphodiesterase 4 (PDE4) isoforms (A-D), part of a family of enzymes known to regulate cyclic adenosine monophosphate levels and immune homeostasis, is elevated compared with healthy controls. Agents that inhibit the enzymatic activity of PDE4, the predominant PDE in most immune cells, exert well-recognized anti-inflammatory effects. Apremilast is a selective PDE4 inhibitor approved for the treatment of adults with moderate to severe plaque psoriasis and/or psoriatic arthritis. In vitro and in vivo investigations have demonstrated the beneficial impact of apremilast treatment on PDE4 activity, inflammatory signal expression, and dermal psoriasiform signs. In patients with moderate to severe psoriasis, treatment with apremilast is associated with significant reductions in plasma levels of interleukin (IL)-17F, IL-17A, IL-22, and tumor necrosis factor-α compared with placebo as early as week 4; decreases in cytokine levels were sustained with continued treatment. Multivariate analyses demonstrated that while changes in IL-17F are the most important predictor of improvement in Psoriasis Area and Severity Index scores, apremilast exerts synergistic attenuating effects among a key group of cytokines involved in the pathology of psoriasis, and these effects correlate with improved skin symptoms. These in vitro and clinical data demonstrate that the beneficial effects of apremilast on known inflammatory mediators are associated with its clinical efficacy. J Drugs Dermatol. 2018;17(8):835-840.

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INTRODUCTION

Psoriasis is a chronic, systemic, inflammatory disease that affects 1% to 4% of the population worldwide,1 including an estimated 7.4 million US adults.2,3 Many patients report that psoriasis has a substantial impact on their quality of life (QOL) because of visible plaques that may be embarrassing, as well as bothersome symptoms, such as itching, flaking, and pain.4 Skin manifestations result from a dysregulated immune response, characterized by an ongoing imbalance in the production of pro-inflammatory and anti-inflammatory cytokines.5,6 Although the initial cause(s) of inflammatory reactivity and imbalance is still not well understood, among the first known disease-related events is keratinocyte recruitment of inflammatory myeloid dendritic cells to the skin, where they release interleukin (IL)-23 and IL-12 to activate IL-17–producing T helper (Th) 17 cells (Th17), Th1 cells, and Th22 cells to produce abundant psoriatic cytokines, including IL-17, tumor necrosis factor (TNF)-α, and IL-22.5-7 These substances, in turn, drive the proliferation and differentiation of keratinocytes associated with epidermal thickening, which underlies skin plaque and nail disease.6 Activated keratinocytes also produce a host of effector substances that recruit other immune cells to the affected skin, establish a positive feedback loop, and exhibit synergistic effects that amplify the inflammatory disease process.5-7With an improved understanding of the complex nature of psoriasis pathophysiology, a range of new therapeutic agents have become available that selectively target and inhibit the activity of pro-inflammatory cytokines such as IL-17 and IL-23, the cell-signaling protein TNF-α, or the phosphodiesterase (PDE) 4 enzyme.8-11 PDEs are the primary means of degrading cyclic adenosine monophosphate (cAMP), an intracellular secondary messenger that regulates inflammatory responses and maintains immune homeostasis; PDEs regulate cAMP concentrations in inflammatory cells, endothelial cells, and keratinocytes.12Agents that inhibit the enzymatic activity of PDE4, the predominant PDE in most immune cells,12 are known to exert anti-inflammatory effects.13,14 Apremilast, a selective PDE4 inhibitor, is approved by the US Food and Drug Administration

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