Apremilast mechanism of action and application to psoriasis and psoriatic arthritis

Abstract

Psoriasis and psoriatic arthritis are common clinical conditions that negatively impact health-related quality of life and are linked to serious medical comorbidities. Disease mechanisms involve local and systemic chronic inflammatory processes. Available biologic therapies specifically target single inflammatory mediators, such as tumor necrosis factor-α (TNF-α), in the context of a larger inflammatory signaling cascade. To interrupt this pathological cascade earlier in the response or further upstream, and return pro-inflammatory and anti-inflammatory signaling to a homeostatic balance, the use of a phosphodiesterase4 (PDE4) inhibitor has been explored. PDE4 is the major enzyme class responsible for the hydrolysis of cyclic adenosine monophosphate (cAMP), an intracellular second messenger that controls a network of pro-inflammatory and anti-inflammatory mediators. With PDE4 inhibition, and the resulting increases in cAMP levels in immune and non-immune cell types, expression of a network of pro-inflammatory and anti-inflammatory mediators can be modulated. Apremilast is an orally available targeted PDE4 inhibitor that modulates a wide array of inflammatory mediators involved in psoriasis and psoriatic arthritis, including decreases in the expression of inducible nitric oxide synthase, TNF-α, and interleukin (IL)-23 and increases IL-10. In phase II studies of subjects with psoriasis and psoriatic arthritis, apremilast reversed features of the inflammatory pathophysiology in skin and joints and significantly reduces clinical symptoms. The use of an oral targeted PDE4 inhibitor for chronic inflammatory diseases, like psoriasis and psoriatic arthritis, represents a novel treatment approach that does not target any single mediator, but rather focuses on restoring a balance of pro-inflammatory and anti-inflammatory signals.

Introduction

Psoriasis is a chronic inflammatory disease predominantly affecting the skin and is estimated to occur in 2–3% of the population [1], [2]. A subset of these psoriasis patients will also develop psoriatic arthritis, a seronegative spondyloarthropathy [3], [4]. In psoriasis and psoriatic arthritis, a dysregulation of multiple pro-inflammatory and anti-inflammatory mediators occurs in dendritic cells, monocytes, macrophages, neutrophils, T cells, B cells, keratinocytes, chondrocytes, and synoviocytes [5], [6]. The cascade of aberrant immune signaling, triggered by stress, physical injury, drugs, or infection, is believed to underlie the clinical signs of inflammation, pain, and pruritus, as well as the histological signs such as keratinocyte hyperproliferation, scaling, and, in subsets of patients, pustular or guttate plaques and nail and joint involvement [5], [7]. Because of the chronic nature of psoriasis and psoriatic arthritis, long-term treatment is often required [8]. Systemic therapies are typically recommended for patients with moderate psoriasis affecting 3–10% of the body surface area, and for severe psoriasis affecting more than 10% of the body surface area, or for patients who experience significant psoriasis-related impairments in quality of life [7], [8], [9]. Traditional systemic or disease-modifying antirheumatic drugs (DMARDs) include methotrexate and cyclosporine; however, these agents are associated with serious organ toxicity and adverse effects and require clinical monitoring throughout treatment [9]. Additionally, evidence for the efficacy of methotrexate in psoriatic arthritis is limited, although methotrexateis often used as a first-line therapy because of its oral route of administration and lower cost, compared with the newer, more effective biologic treatments [3]. These biologic therapies include inhibitors of tumor necrosis factor-alpha (TNF-α), interleukin 12 and 23 (IL-12/IL-23), and antibodies that target B cells or T cells [7], [8]. Although biologic therapies represent an advance in the treatment of chronic inflammatory diseases, their use is limited by treatment resistance (including both initial lack of efficacy and loss of effect), tolerability issues, parenteral administration, and barriers to patient access, such as high cost and specialist management [7], [8]. Research efforts continue in the search for oral treatment options that are safe and effective in the treatment of psoriasis and psoriatic arthritis.