Effect of Adalimumab on Gene Expression Profiles of Psoriatic Skin and Blood

August 2016 | Volume 15 | Issue 8 | Original Article | 988 | Copyright © August 2016


Maggie Chow MD PhD,a Kevin Lai MS,b Richard Ahn PhD,b Rashmi Gupta PhD,b Sarah Arron MD PhD,b and Wilson Liao MDb

aUniversity of Southern California, Keck School of Medicine, Department of Dermatology, Los Angeles, CA
bUniversity of San Francisco, California, Department of Dermatology, San Francisco, CA

Abstract
BACKGROUND: Adalimumab is an anti-TNF biologic drug that is efficacious in the treatment of psoriasis. However, the effect of adalimumab on genome-wide gene expression changes in skin and peripheral blood is not well characterized.
METHODS: Thirty adult subjects with > 10% body surface area of chronic plaque psoriasis were recruited for the study. Lesional skin and peripheral blood mononuclear cell samples prior to and one month following treatment with adalimumab were collected. The skin samples were analyzed using genome-wide RNAseq, and the blood samples were analyzed using genome-wide Affymetrix microarrays. Data preprocessing and analysis were conducted using the EdgeR and Affy packages in R/Bioconductor.
RESULTS: In the skin, paired analysis before and after treatment revealed changes in pathways important to epidermal development and keratinocyte differentiation. Such important genes as keratin 6A and 6B, tubulin B6, desmocollin, and desmoglein 3 were among the top differentially expressed genes. In peripheral blood, pathways involved in hematopoetic cell lineage and immune response were found to be differentially expressed, including genes such as the Fc receptor-like A and 5, as well as immunoglobulin heavy chains. Using a principal components approach, we show that expression of genes in post-treatment skin more closely resembles that of healthy controls.
CONCLUSION: Treatment of psoriasis with adalimumab appears to be associated with modulation of keratinocyte and epidermal proliferation in the skin and with immunologic changes in the blood. We discuss the ramifications of these findings for the treatment for psoriasis.

J Drugs Dermatol. 2016;15(8):988-994.

INTRODUCTION

Psoriasis is a chronic systemic inflammatory disease with cutaneous manifestations known to have an immune-mediated etiology. It is characterized by hyperproliferative epidermis and a mixed cutaneous lymphocytic infiltrate.1 This disease can have severely negative impact on patient quality of life.2–5
Though traditional systemic therapies have been shown to be effective for psoriasis, they are also associated with abundant side effects.2 Because of the limitations of traditional systemic therapies, newer biologic agents have shown promise in targeting specific cytokines in the inflammatory cascade thought to precipitate psoriasis. Of these biologic agents, therapies targeting tumor necrosis factor (TNF) have shown particular efficacy.6 TNF is a cytokine that plays multiple roles in the development and maintenance of psoriasis, include recruiting T cells to the skin and increasing the proliferation of keratinocytes.7
Adalimumab is an IgG1 isotype of a human monoclonal antibody that binds specifically with high affinity to human TNF.8 Adalimumab blocks the interaction of TNF with the p55 and p75 cell surface TNF receptors, thereby neutralizing TNF-mediated pathways.9 It has been shown to be efficacious in treating moderate to severe psoriasis in randomized controlled trials.6,10–12 Adalimumab may even be more effective than other systemic therapies, such as etanercept.13–15
Recently, Bose et al (2013) examined the effect of anti-TNF therapy in skin and blood by cytokine assay and RTPCR. Surprisingly, they found that cytokines such as IL17, IL10, and IFN-gamma increased their expression in the peripheral blood following therapy. Additionally, the proliferative response of CD4+ T cells to TCR stimulation was enhanced. In the skin, in contrast, the expression of Th17/Th1 cytokine and early inflammatory genes were decreased in expression following treatment. The authors asserted that inhibition of the CCR7/CCL19 axis in lesional skin is an important event for the efficacy of treating psoriasis. These results have been replicated by other authors.16
In another study using RTPCR to investigate the effect of adalimumab on the key drivers in the pathogenesis of psoriasis, markers for innate immunity and epidermal differentiation and proliferation in psoriatic skin were rapidly restored to normal levels. In contrast, the genes of the adaptive immune system normalized in a delayed fashion.17
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