Recent advances in the treatment of skin involvement in systemic sclerosis

Asano Inflammation and Regeneration (2017) 37:12 DOI 10.1186/s41232-017-0047-4 Inflammation and Regeneration REVIEW Open Access Recent advances in the treatment of skin involvement in systemic sclerosis Yoshihide Asano Abstract Skin fibrosis is a devastating clinical condition commonly seen in skin-restricted and systemic disorders. The goal of skin fibrosis treatment is the restoration of abnormally activated dermal fibroblasts producing the excessive amount of extracellular matrix, which is generally a final consequence of the complex disease process including the activation of vascular and immune systems. Among various skin fibrotic conditions, the molecular mechanisms underlying dermal fibroblast activation have been mostly well studied in systemic sclerosis (SSc). SSc is a multisystem autoimmune and vascular disease resulting in extensive fibrosis of the skin and various internal organs. Since SSc pathogenesis is believed to include all the critical components regulating tissue fibrosis, the studies on anti-fibrotic drugs against SSc provide us much useful information regarding the strategy for the treatment of various skin fibrotic conditions. In the recent decade, as is the case with other autoimmune and inflammatory diseases, the molecular targeting therapy with monoclonal antibody has been clinically well examined in SSc. Promising clinical outcomes are so far reported in tocilizumab (an anti-IL-6 receptor antibody), rituximab (an anti-CD20 antibody), and fresolimumab (an anti-TGF-β antibody). The analysis of gene expression profiles in skin lesions of SSc patients treated with tocilizumab or fresolimumab revealed a critical role of monocyte-macrophage lineage cells in the development of skin fibrosis and the involvement of IL-6 and TGF-β in the activation of those cells. Considering that B cells modulate the differentiation and activation of macrophages, favorable clinical outcomes of rituximab treatment imply the central role of B cell/monocyte-macrophage lineage cell axis in the pathogenesis of SSc. This scenario may be applicable at least partly to other skin fibrotic conditions. In this review article, the currently available data on these drugs are summarized and the future directions are discussed. Background Skin fibrosis is a devastating clinical condition resulting in severe disability and seriously affecting morbidity, which commonly occurs in skin-restricted and systemic disorders, including systemic sclerosis (SSc), localized scleroderma, and chronic graft-versus-host disease. It is widely accepted that constitutively activated dermal fibroblasts play a crucial role in the development and maintenance of skin fibrosis through the production of excessive amount of extracelluar matrix, but anti-fibrotic therapies targeting those cells generally elicit a limited effect on this pathological condition. In a sense, this is plausible because fibroblasts manifest a pro-fibrotic phenotype as a final consequence of the complex disease process consisting of complicated cell-cell interactions Correspondence: Department of Dermatology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan and networks of soluble factors. For instance, the fibrotic skin condition is generally related to T helper (Th)2/ Th17-skewed immune polarization [1, 2], M2 macrophage differentiation [3], increased infiltration of plasmacytoid dendritic cells [4], increased endothelial intercellular adhesion molecule-1 expression [5], endothelial-to-mesenchymal transition [6], epithelial cell activation [7], and/or adipocyte-myofibroblast transdifferentiation [8]. In particular, autoimmunity and/or inflammation seem to play a central role because corticosteroids and/or immunosuppressants are effective for most of the skin fibrotic disorders even though clinical outcomes are variable in individual cases. Therefore, immune cells and several key molecules are the critical targets to interfere with the complex disease process underlying skin fibrosis. The molecular targeting therapy has recently caught much attention to achieve this goal and also would be helpful to further understand the © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Asano Inflammation and Regeneration (2017) 37:12 pathogenesis of this clinical entity when favorable outcomes are obtained. Among skin fibrotic conditions, the molecular mechanisms resulting in dermal fibroblast activation have been mostly well studied in SSc. SSc is characterized by extensive dermal fibrosis following aberrant activation of immune and vascular systems, in which all the critical components regulating tissue fibrosis are included [9, 10]. Therefore, the studies on anti-fibrotic drugs against SSc provide us much useful information regarding the strategy for the treatment of various skin fibrotic conditions. In the recent decade, as is the case with other autoimmune and inflammatory diseases, the molecular targeting therapy with monoclonal antibody has been clinically well examined in SSc. Promising clinical outcomes have been reported in tocilizumab (an antiinterleukin-6 (IL-6) receptor antibody), rituximab (an anti-CD20 antibody), and fresolimumab (an antitransforming growth factor (TGF)-β antibody). In this review article, the currently available data on these drugs are summarized and the future directions are discussed. Tocilizumab The role of IL-6 in SSc Increasing evidence suggests a critical contribution of IL-6 to the development of tissue fibrosis and vasculopathy as well as inflammation associated with SSc. First, IL-6 is much more abundantly expressed in various types of cells, including dermal fibroblasts, dermal microvascular endothelial cells, inflammatory cells, and keratinocytes, of SSc lesional skin than in those cells of healthy control skin [11]. Consistently, the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which is induced by the activation of IL-6 receptor/gp130 complex, is broadly detectable in various cell types, most remarkably in dermal microvascular endothelial cells, of SSc lesional skin irrespective of disease subtypes and disease duration, while totally absent or marginal in any cell types of healthy control skin [12]. More importantly, the elevation of serum IL-6 levels is associated with poor prognosis of this disease [11]. In in vitro studies SSc dermal fibroblasts seem to be ac (...truncated)