Future treatments in systemic sclerosis.
Systemic sclerosis (SSc) is an autoimmune disorder with clinical manifestations resulting from immune activation, fibrosis development and damage of small blood vessels. Although there have been no established treatments for SSc, lots of new treatments targeting organ and pathogenesis are in the process of development. Transforming growth factor (TGF)-beta is a major cytokine involved in the pathogenesis of fibrosis in SSc. The blockade of cell surface molecules capable of activating latent TGF-beta, blockade of ligand by the pan-isoform-specific antibody, soluble TGF-beta receptors and a recombinant latency associated peptide, as well as inhibitors for ALK5 and Smad3 are the potential strategies to abolish the pathological activation of TGF-beta signaling in SSc fibroblasts. Besides TGF-beta, connective tissue growth factor (CTGF)/CCN2, platelet-derived growth factor (PDGF) and endothelin-1 are the candidates for the new therapeutic targets. As for immune dysfunction in SSc, i.v. immunoglobulin infusion, stem cell transplantation and B-cell depletion are potential new therapies under or awaiting a randomized, double-blind, placebo-controlled trial, although their efficacies are still controversial. Phosphodiesterase-5 inhibitors, endothelin receptor antagonists and inhibitors for serotonin signaling are the new therapeutic targets for Raynaud's phenomenon, digital ulceration and pulmonary arterial hypertension in SSc. Imatinib mesylate may be a novel new therapy for fibrosis and vasculopathy in SSc because it reverses the expression levels of Fli1, which is a transcription factor downregulated in SSc through an epigenetic mechanism and is likely to be involved in the development of fibrosis and vasculopathy in this disease. Potential therapeutic targets other than those described above are also reviewed.
Asano
Yoshihide
Y
Department of Dermatology, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan. yasano-tky@umin.ac.jp
D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D001402:B-Lymphocytes / Q000276:immunology; D001549:Benzamides; D055513:Connective Tissue Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors / Q000276:immunology; D006801:Humans; D000068877:Imatinib Mesylate; D007136:Immunoglobulins / Q000627:therapeutic use; D051379:Mice; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000276:immunology; D011743:Pyrimidines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D051900:Smad3 Protein / Q000037:antagonists & inhibitors / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology
D001549:Benzamides; D055513:Connective Tissue Growth Factor; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D000068877:Imatinib Mesylate; D007136:Immunoglobulins; D058986:Phosphodiesterase 5 Inhibitors; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D011743:Pyrimidines; D018125:Receptors, Transforming Growth Factor beta; D017367:Selective Serotonin Reuptake Inhibitors; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta