Session Type: ACR Concurrent Abstract Session
Session Time: 9:00AM-10:30AM
Systemic sclerosis (SSc) is a chronic fibrosing disorder that affects the skin and other internal organs. Inflammation, vasculopathy and fibrosis at the affected area are the major pathological aspects of SSc. Infiltration of inflammatory cells into the fibrotic lesions often occurs at an early phase of the disease; therefore, immunosuppressive therapy often prevents disease progression and accumulation of extracellular matrix (ECM) molecules. The PDE4 inhibitor, apremilast, acts on target cells as an anti-inflammatory agent by increasing intracellular cAMP levels and the subsequent activation of protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac). cAMP-elevating molecules have been extensively reported to ameliorate fibrosis in various fibrotic models. Based on these findings, we hypothesized that apremilast may prevent the progression of dermal fibrosis by inhibiting inflammation and fibrosis.
Methods: Dermal fibroblasts obtained from healthy individuals and patients with diffuse cutaneous SSc were incubated with apremilast at a concentration of 1-10 μM in the presence or absence of TGF-β1. Furthermore, to assess the anti-fibrotic effect of apremilast in vivo, we injected BALB/c mice with bleomycin together with intraperioneal administration of PBS or apremilast (1 mg/kg or 5 mg/kg daily) for 4 weeks, and dermal fibrosis was evaluated by the degree of skin thickness, αSMA-positive myofibroblast counts and collagen content. Intracellular cAMP levels were determined by an enzyme-linked immunosorbent assay (ELISA). mRNA levels of target molecules were determined by quantitative RT-PCR. Protein levels of target molecules were determined by immunoblotting and immunostaining.
Results: PDE4A, B and D were expressed in human dermal fibroblasts, and the mRNA levels of PDE4 subtypes did not differ between fibroblasts from healthy and SSc groups. Apremilast significantly suppressed the expression of COL1A1, COL1A2 and CTGF mRNA in SSc dermal fibroblasts and healthy dermal fibroblasts treated with TGF-β1. Similarly, apremilast decreased the protein levels of type I collagen and CTGF in SSc dermal fibroblasts. With respect to the signal transduction of TGF-β1, phosphorylated Smad3, ERK1/2 and Akt were diminished in dermal fibroblasts treated with apremilast. These findings demonstrated that apremilast inhibited the production of ECM proteins by interfering with TGF-β signaling in both a Smad-dependent and a Smad-independent manner in dermal fibroblasts. Furthermore, in an in vivo analysis of a mouse model of bleomycin-induced dermal fibrosis, apremilast attenuated the development of dermal fibrosis compared with PBS.
Conclusion: Apremilast has anti-fibrotic effects on experimental dermal fibrosis, at least in part, by acting on activated dermal fibroblasts. Considering that apremilast is approved for psoriatic arthritis, apremilast may serve as a well-tolerated drug for the treatment of fibrotic lesions in patients with SSc.
To cite this abstract in AMA style:Higuchi T, Kawaguchi Y, Takagi K, Tochimoto A, Ichimura Y, Katsumata Y, Ichida H, Kawasumi H, Nishina H, Tochihara M, Nishino A, Hirahara S, Moriyama R, Yamanaka H. Apremilast Attenuates the Fibrogenic Phenotype of Dermal Fibroblasts from Patients with Systemic Sclerosis, Contributing to the Prevention of the Progression of Experimental Dermal Fibrosis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/apremilast-attenuates-the-fibrogenic-phenotype-of-dermal-fibroblasts-from-patients-with-systemic-sclerosis-contributing-to-the-prevention-of-the-progression-of-experimental-dermal-fibrosis/. Accessed November 25, 2020.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/apremilast-attenuates-the-fibrogenic-phenotype-of-dermal-fibroblasts-from-patients-with-systemic-sclerosis-contributing-to-the-prevention-of-the-progression-of-experimental-dermal-fibrosis/