Mechanisms Underlying the Clinical Effects of Apremilast for Psoriasis

for the treatment of adult patients with moderate to severe plaque psoriasis, as well as patients with psoriatic arthritis.¹⁵ With apremilast-mediated inhibition of PDE4, cAMP levels become elevated, causing reduced expression of inflammatory signals central to the psoriatic disease process, such as IL-17, IL-23, and TNF-α, while at the same time causing increased expression of anti-inflammatory cytokines, such as IL-10.16,17 The current review provides an overview of physiological mechanisms by which apremilast works to interrupt the psoriatic inflammatory cascade and helps to reduce the clinical signs and symptoms of disease activity.

Because psoriasis is characterized by an intense inflammatory infiltrate in the dermis, it is relevant to evaluate the expression of PDE4 in psoriatic dermis. In a recent set of experiments, PDE4 isoforms were shown to be expressed more in diseased skin (including psoriasis, atopic dermatitis, and discoid lupus erythematosus) than in normal skin; in psoriatic skin, the largest consistent increases were observed in the endothelium (PDE4A and PDE4D) and fibroblasts (PDE4A, PDE4B, and PDE4D).¹⁸ PDE4B expression was prominently greater in the vessels of the superficial dermis of patients with psoriasis compared with healthy controls, as well as in inflammatory cells, which were more abundant in psoriatic skin.¹⁸ In vitro, PDE4B and PDE4D expression were significantly upregulated (5.4-fold higher and 2.2-fold higher, respectively) in peripheral blood mononuclear cells (PBMCs) in patients with psoriasis compared with healthy controls.18 Fibroblasts and, to a greater extent, the more differentiated myofibroblasts, express all PDE4 isoforms at the mRNA and protein level.¹⁸ The elevated PDE4 levels observed in psoriatic blood and tissues strongly suggest that the pro-inflammatory, PDE4-mediated degradation of cAMP likely plays a role in psoriasis pathology.T cells are central mediators of the systemic and local inflammation in psoriasis and psoriatic arthritis.¹⁹ Apremilast was shown in T-cell cultures to inhibit a number of Th1, Th2, and Th17 cytokines to differing degrees. Apremilast most potently inhibited IL-17, recognized as a cornerstone of the Th17 response that is characteristic of psoriasis and psoriatic arthritis.²⁰ Also inhibited were the Th2 cytokines IL-5, IL-10, and IL-13, and less potently, TNF-α and the Th1 cytokines granulocyte-macrophage colony-stimulating factor and interferon-γ.¹⁶ These results indicate that IL-17 production by T cells is quite dependent upon PDE4 enzymatic activity and is very sensitive to PDE4 inhibition by apremilast.Neutrophils are another component of psoriatic inflammatory cell infiltrates, and one of the main downstream responders to the IL-17 produced by T cells. Apremilast treatment was found to directly inhibit neutrophil responses, including the reduced production of various chemoattractant molecules such as IL-8, CD18, CD11b, and leukotriene B4, and decreased neutrophil chemotaxis and adhesion to endothelial cells.¹⁷Recent studies have uncovered a functional role for PDE4 in differentiated myofibroblasts. Of interest, PDE4 co-immunoprecipitates with the nerve growth factor (NGF) receptor CD271, while apremilast inhibits cell death induced by β-amyloid, a ligand of CD271, in these cells.^18,21 In addition, apremilast decreases NGF-induced fibroblast migration and significantly reduces cAMP degradation induced by β-amyloid.18 PDE4s therefore have a key role in the pathophysiology of psoriasis, and PDE4/CD271 plays an important role in modulating fibroblast functions, including fibrotic processes and wound healing.¹⁸A functional role for PDE4 has also been observed in keratinocytes. Firstly, PDE4 isoforms are expressed in all keratinocyte subpopulations (stem, transit amplifying, and post-mitotic), while CD271 is only detected in transit amplifying cells.²¹ Secondly, all PDE4 isoforms co-immunoprecipitate with CD271 in keratinocytes (most likely transit amplifying cells).²¹ Apremilast inhibits NGF-induced proliferation and reduces growth arrest and apoptosis induced by the CD271 ligand β-amyloid in human keratinocytes.²¹ cAMP degradation is prevented by the addition of a PDE4 inhibitor alone or in combination with an NGF receptor, as shown in cell culture supernatants (enzyme-linked immunosorbent assay).²¹ Apremilast also counteracts cAMP degradation induced by β-amyloid.21 Furthermore, PDE4 inhibition induces upregulation of IL-10 and normalizes IL-10 levels reduced by β-amyloid.21 On the other hand, apremilast decreases β-amyloid-induced upregulation of IL-8 and IL-1β levels.²¹ With apremilast treatment, normal human epidermal keratinocytes exhibit decreased expression of TNF-α while continuing to show cell viability and proliferation.17 Schafer et al also recently showed that apremilast modulates inflammatory gene expression in normal human keratinocytes stimulated by IL-17, marked by reductions in expression of gene encoding the cytokines IL-12/IL-23p40, IL-19, IL-31, and IL-33, as well as the alarmins S100A7, S100A8, and S100A12 (Celgene, data on file). Collectively, these data suggest that PDE4 regulates keratinocyte functions via signaling pathways involving receptors such as CD27121 and IL-17 (Celgene, data on file).In immunodeficient mice xenotransplanted with normal human skin and triggered with human psoriatic natural killer (NK) cells, treatment with oral apremilast was associated with morphological normalization of the epidermis, marked histologically by significant reductions in epidermal thickness and a decreased proliferation index (versus vehicle-treated groups), and the absence of lymphocyte infiltration.¹⁷ Findings with apremilast were generally similar to those observed