The Biological Rationale for Use of Vitamin D Analogs in Combination With Corticosteroids for the Topical Treatment of Plaque Psoriasis

August 2013 | Volume 12 | Issue 8 | Original Article | 129 | Copyright © August 2013


Siegfried Segaert MD PhDa and Mads Røpke PhDb

aUniversity Hospital Leuven, Leuven, Belgium
bLEO Pharma, Ballerup, Denmark

Abstract
Topical corticosteroids and vitamin D analogs are well established as safe and effective first-line treatments for mild to moderate plaque psoriasis. They act via distinct and complementary mechanisms of action: vitamin D analogs primarily counter epidermal dysregulation, inhibiting epidermal hyperproliferation and inducing keratinocyte differentiation, whereas corticosteroids act primarily as immunosuppressors, targeting pro-inflammatory cytokines and chemokines. Furthermore, both agents have additional activity that may complement their main effects: vitamin D analogs have some immunomodulatory properties and corticosteroids may impact on keratinocyte differentiation. Based on their dominant mechanisms of action, there is a strong scientific rationale for the combination of corticosteroids and vitamin D analogs in the treatment of plaque psoriasis. Indeed, the combination has been shown to have a greater effect on the immune-mediated mechanisms of psoriasis than either monotherapy used alone. There is also a strong biological rationale for decreased side effects with the combination. Vitamin D may restore epidermal barrier function, which is impaired with corticosteroid use, and counteract steroid-induced skin atrophy. Corticosteroids may reduce perilesional skin irritation induced by vitamin D analogs. Although clinical data strongly support improved efficacy and tolerability with a combination of calcipotriol and betamethasone dipropionate, additional studies are needed to further investigate their underlying mechanisms.

J Drugs Dermatol. 2013;12(8):e129-e137.

INTRODUCTION

Psoriasis is an immune-mediated, chronic inflammatory skin disease clinically characterized by well-defined, raised, red, and scaly plaques.1,2 Topical therapies are the standard first-line treatment for mild to moderate plaque psoriasis, including corticosteroids and vitamin D analogs, which are proven, well-established, well-tolerated, effective monotherapies. 3 However, topical corticosteroids cause skin atrophy and striae4-7 and are associated with perceived tachyphylaxis8,9 in patients with psoriasis. Vitamin D analogs are associated with perilesional skin irritation in psoriasis.8,10
Beyond their use as monotherapies, improved efficacy and tolerability have been demonstrated with concurrent corticosteroid and vitamin D analog use in several studies, which provided the rationale for development of a single-application combination product.11-15 Indeed, a 2-compound product combining calcipotriol 50 μg/g and betamethasone dipropionate 0.5 mg/g is available in ointment and gel formulations, permitting simultaneous once-daily dosing.16,17 Clinical trials showed improved efficacy compared with either monotherapy and improved tolerability compared with calcipotriol.18 Consequently, the combination ointment and gel are now recommended as first-line treatment for mild to moderate plaque psoriasis in national guidelines19-21 and according to an expert consensus panel.22
This review explores the biological rationale for combination of topical corticosteroids and vitamin D analogs in the treatment of plaque psoriasis, with a particular focus on their distinct mechanisms of action and complementary effects. Evidence for translation of this rationale into clinical benefit is also discussed.

Pathogenesis

Histologically, psoriasis is characterized by epidermal hyperproliferation with incomplete keratinocyte differentiation, infiltration of inflammatory cells into the dermis and epidermis, and increased vascularity in the dermis.1,2,23 Figure 1 illustrates current understanding of psoriasis pathogenesis, as described below.2
Psoriasis is initiated by dermal dendritic cell (DC) activation, which occurs by mechanisms that are not yet fully elucidated. DCs capture, process, and present antigen to naïve T-cells in order to initiate an immune response against the antigenic material. Normally, self-antigens are tolerated; however, in psoriasis, self-DNA triggers DC activation when it is bound by the antimicrobial peptide LL-37.24 Environmental and/or genetic factors may also influence DC activation and predispose an individual to the disease. Activated DCs migrate into the draining lymph nodes where they induce differentiation of naïve T-cells into effector T-cells. In psoriasis, these include T-helper
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