Review Article

Small Molecules in the Treatment of Psoriasis

DDR

DRUG DEVELOPMENT RESEARCH 76 : 215–227 (2015)

Tiago Torres1,2* and Paulo Filipe3 Department of Dermatology, Centro Hospitalar do Porto, Portugal 2 Instituto de Cie^ncias Biomedicas Abel Salazar, University of Porto, Portugal 3 Dermatology Research Unit, Instituto de Medicina Molecular, University of Lisbon, Portugal 1

Strategy, Management and Health Policy Enabling Technology, Genomics, Proteomics

Preclinical Research

Preclinical Development Toxicology, Formulation Drug Delivery, Pharmacokinetics

Clinical Development Phases I-III Regulatory, Quality, Manufacturing

Postmarketing Phase IV

ABSTRACT Psoriasis is an inflammatory systemic skin disease that affects various parts of the body requiring long-term management due to its chronic nature. Available treatment options include topical, systemic or biological therapies, which have long-term limitations associated to toxicity, tolerability and risk for adverse effects requiring its intermittent use and close monitoring. Small molecules modulate proinflammatory cytokines, selectively inhibit signaling pathways and showing potential to treat inflammatory diseases in patients not responding to conventional treatments. Presently, small molecules available are phosphodiesterase 4 inhibitors or Janus kinase inhibitors. Other small molecules under development for psoriasis include fumaric acid esters, amygdalin analogs, protein kinase C inhibitors, mitogen-activated protein kinase inhibitors, spleen protein kinase inhibitors, other tyrosine kinase inhibitors, sphingosine 1-phosphate receptor agonists, and A3 adenosine receptor agonists. These new treatment options represent important advances in the development of specific drugs to respond to the C 2015 V goals of treatment and improve patient quality of life. Drug Dev Res 76 : 215–227, 2015. Wiley Periodicals, Inc.

Key words: psoriasis; apremilast; tofacinib

INTRODUCTION

Psoriasis is a chronic, inflammatory, immunemediated, systemic disease of skin and joints characterized by erythematous, scaly patches, or plaques on the skin resulting from hyperproliferation of epidermal keratinocytes [Schafer, 2012; Flatz and Conrad, 2013; Ports et al., 2013]. Affecting approximately 2% of the world population, psoriasis may present lesions on the scalp, trunk, and extensor surfaces [Boy et al., 2009; Declercq and Pouliot, 2013; Perez, 2013; Belge et al., 2014; Mease and Armstrong, 2014]. This is associated with a significantly impaired quality of life and coexisting comorbidities, causing physical discomfort with limitations in daily activities and productivity, psychosocial problems, and emotional distress [Papp et al., 2012a,b; Strand et al., 2013; Belge et al., 2014; Mease and Armstrong, 2014]. C 2015 Wiley Periodicals, Inc. V

Because of the chronic nature of psoriasis, long-term management is often necessary. However, available options may only clear the skin temporarily. Independently of adverse effects, all therapeutic options have limitations, so the development of new therapies is of utmost importance [Schafer, 2012; Garcıa-Perez et al., 2013]. Psoriasis presents a genetic predisposition caused by dysregulation of multiple inflammatory

*Correspondence to: Centro Hospitalar do Porto, Servic¸o de Dermatologia, Rua D. Manuel II, s/n, Porto, Portugal, 4100 Porto [email protected] Received 26 June 2015; Accepted 14 July 2015 Published online in Wiley Online Library (wileyonlinelibrary. com). DOI: 10.1002/ddr.21263

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TORRES AND FILIPE

mediators [Schafer, 2012; Rahman et al., 2012; Declercq and Pouliot, 2013; Flatz and Conrad, 2013]. The immunopathogenesis of psoriasis is complex and involves changes in the innate (keratinocytes, dendritic cells, macrophages, neutrophils, monocytes and endothelial cells) and acquired immune systems (T lymphocytes). Both immunologic systems interact with each other producing cytokines, chemokines, and growth factors. Triggers such as stress, injury, drugs, and infection start the inflammatory process culminating in keratinocytes hyperproliferation [Abdelnoor 2009; Rahman et al., 2012; Schafer, 2012; Patel et al., 2012; Papp et al., 2012a; Declercq and Pouliot, 2013; Flatz and Conrad, 2013; Mease and Armstrong, 2014]. First, there is activation of the innate immune system cells (keratinocytes and dendritic cells) with proinflammatory cytokines release such as tumour necrosis factor-a (TNF-a) and interleukins (IL). Consequently, antigen-presenting cells (Langerhans cells) are also activated in epidermis and dermis. These cells migrate to regional lymph nodes and start T lymphocytes activation process [Rahman et al., 2012; Declercq and Pouliot, 2013; Flatz and Conrad, 2013; Garcıa-Perez et al., 2013]. Once activated, lymphocytes differentiate into three mainly subtypes: T lymphocyte CD41 (INF-c, TNF-a, and IL-2 producers), Th17 lymphocyte (TNF-a, IL-6, and IL-22 producers), and T lymphocyte CD81 (INF-c, TNF-a, perforin, and B granzime producers). These then return to the skin via the mediation of adhesion molecules, stimulating and perpetuating the inflammatory process by interaction with other cells such as macrophages, dendritic cells, keratinocytes and neutrophils. It is clear that genetic, environmental, and inflammatory mechanisms are crucial for psoriasis development. Thus, the knowledge of psoriasis’ pathogenesis and inherent inflammatory mechanisms play an important role in the understanding process for the development of new and more specific drugs to improve patient’s quality of life. Available Treatments for Psoriasis As an incurable disease, the main goal of psoriasis treatment would be to clear the skin lesions and prevent its recurrence, while providing patients better health-related quality of life (HRQOL). However, the choice of treatment depends on severity and extent of skin lesion exposure. Conventional treatments for psoriasis include topical or systemic therapies. Topical treatments include corticosteroids, the most common drug preDrug Dev. Res.

scribed for patients with mild-to-moderate psoriasis, vitamin D analogs, retinoids, or phototherapy. However, these treatments have variable efficacies and in the long term can have severe side effects associated [Patel et al., 2012; Rahman et al., 2012; Perez, 2013; Ports et al. 2013; Hsu and Armstrong, 2014]. Systemic treatments are used when patients are refractory to topical treatments and phototherapy, when skin lesion exposure is too extensive or in patients with significant impairments in quality of life [Schafer, 2012; Perez, 2013]. Often added with topical therapies, systemic therapies include retinoids, methotrexate, cyclosporine, and acitretin. These agents are associated with high toxicity and adverse effects requiring an intermittent use and close monitoring throughout treatment [Schafer, 2012; Perez, 2013; Ports et al. 2013]. In the past several years, biological therapies like infliximab, etanercept, adalimumab, or ustekinumab have appeared as good options for the treatment of moderate to severe psoriasis with proven efficacy and safety profiles. Biologic therapies act by blocking the action of T-cells, TNF-a, or ILs 12 and 23 [Patel et al., 2012; Schafer, 2012; Perez, 2013]. However, their use is limited by treatment resistance, long-term tolerability, systemic routes of administration (subcutaneous/intravenous), potential risk for adverse events (AEs) and high cost [Schafer, 2012; Perez, 2013; Strand et al. 2013; Hsu and Armstrong, 2014].These limitations emphasize the need for additional treatment options for psoriasis, which can respond to the goals of treatment and additionally enhance HRQOL. Small-molecular-weight inhibitors have been explored as novel orally administered drugs that modulate proinflammatory cytokines, specifically targeting the IL-23/Th17 pathway, showing potential to treat inflammatory diseases [Rahman et al., 2012; Patel et al., 2012; Aslam and Griffiths, 2014]. Small Molecules Small molecules are small-molecular-weight inhibitors (

Small Molecules in the Treatment of Psoriasis.

Preclinical Research Psoriasis is an inflammatory systemic skin disease that affects various parts of the body requiring long-term management due to i...
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