CommentaryApremilast mechanism of action and application to psoriasis and psoriatic arthritis
Graphical abstract
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.
Section snippets
Pathophysiology of psoriasis and dermatologic inflammation
Acute inflammatory reactions typically occur in response to infection and are coupled with the release of local factors that prevent excessive trafficking of leukocytes, allowing for resolution of inflammation. Resolution of an acute inflammatory response within the local tissues and a re-establishment of immunological homeostasis are necessary for ongoing health [10]. Skin is an important site for antigen presentation, and epidermal Langerhans cells and dermal dendritic cells play pivotal
Role of cAMP and PDE4 in regulating inflammation
One limitation of currently available biologic agents is that they do not reach inside the cell to target intracellular signaling pathways. Instead, such agents are antibodies or compounds that selectively bind with receptors or proteins on extracellular membranes or extracellular milieu (e.g. anti-TNF), altering activity of targeted cell types, cell-to-cell interactions, and immune signaling [5]. Biologic agents tend to specifically target a single pro-inflammatory marker and interrupt the
Apremilast in vitro pharmacology and activity in nonclinical models relevant to psoriasis
PDE4 inhibitors are a class of low molecular weight compounds that exhibit anti-inflammatory effects in several preclinical models [27], [48] and clinically with various chronic inflammatory diseases, including psoriasis [49], psoriatic arthritis [50], atopic dermatitis [51], and inflammatory bowel disease [52]. Apremilast is a novel, orally available small molecule that specifically targets PDE4 [53]. Through this targeted inhibition, apremilast elevates intracellular cAMP levels, partially
Apremilast pharmacology in nonclinical models and cell types relevant to arthritis
In human rheumatoid synovial membrane cells, apremilast reduced spontaneous TNF-α production in a concentration-dependent manner [56]. In two murine models of arthritis (anti-type II collagen monoclonal antibody and immunization with type II collagen), apremilast significantly reduced the clinical score and maintained a healthy joint architecture in a dose-dependent manner. Histopathological examination of the affected joints in the collagen antibody-induced arthritis model indicated that
Clinical profile of the PDE4 modulator apremilast and linkage to the mechanism of psoriatic disease
Several characteristics of apremilast contribute to its differentiation from other PDE4 modulators. Unlike cilomilast, which has demonstrated 10-fold more selectivity for PDE4D (versus PDE A, B, or C), apremilast does not demonstrate any marked selectivity for the PDE4D subfamily [55]. This may be clinically important, because the PDE4D isozyme has been associated with the behavioral correlate of emesis in mice [64]. The lack of PDE4D selectivity of apremilast may in part explain its improved
Conclusions
In recent years, researchers have gained key insights into the pathogenesis of psoriatic disease, which have highlighted the central role of aberrant immune cell signaling and chronic inflammation. It is believed that environmental triggering factors, such as stress, infection, injury, or drugs, initiate differentiation and activation of dendritic antigen-presenting cells, prompting their interaction with adaptive immune system T cells and promoting increased expression of numerous
Acknowledgments
The author received editorial support in the preparation of this manuscript from Peloton Advantage, funded by Celgene Corporation. Dr. Peter Schafer is an employee of Celgene Corporation.
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