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A sweeter approach to treating scleroderma?

DII small banner By Warren R. Heymann, MD
March 14, 2017

Scleroderma fingernail changes. A, Longitudinal ridging and pitting. B, Brachyonychia. C, Trachyonychia. D, Thickened and enlarged cuticles. E, Thickened, enlarged, and irregular cuticles. F, Nailfold capillaroscopy: presence of enlarged and giant capillaries. G, Nailfold capillaroscopy: presence of enlarged and giant capillaries, loss of capillaries, and disorganization of microvascular array.
Credit: JAAD
We’re like licorice. Not everybody likes licorice, but the people who like licorice really like licorice Jerry Garcia

Patients with scleroderma may learn to love licorice.
Treating scleroderma is a difficult task. The pathogenesis of scleroderma is based on the interplay of autoimmunity, vasculopathy, and fibrosis. According to Aringer and Erler, “Most rheumatologists would agree that systemic sclerosis (SSc) still can be a dreadful disease and that the advances we see in other areas have not yet arrived.” They outline current and impending therapies that may be useful in addressing each contributory component of the pathogenic triad: 1) autoimmunity (cyclophosphamide, azathioprine, mycophenolate mofetil, rituximab, tocilizumab, autologous stem cell transfer; 2) vasculopathy (ACE inhibitors, bosentan, iloprost, sildenafil); and 3) fibrosis (nintedanib) (1).

There may be a medication that addresses all 3 components of scleroderma — glycyrrhizin — the active ingredient of licorice.

Glycyrrhiza glabra has been used medicinally since antiquity and such use has been well documented in written form starting with the ancient Greeks. Glycyrrhizin is the major active constituent obtained from licorice roots, one of the most widely used herbs for the treating liver disease. The plant is used as an anti-inflammatory, spasmolytic, laxative, anti-depressive, anti-ulcer and anti-diabetic agent (2).

Yamashita et al studied the potential impact of glycyrrhizin on the key pathological manifestations of SSc, including inflammation, vasculopathy, and tissue fibrosis. They utilized bleomycin-treated mice mimicking the fibrotic and inflammatory components of SSc and endothelial cell-specific Fli1-knockout mice recapitulating SSc vasculopathy. Glycyrrhizin significantly ameliorated dermal fibrosis in bleomycin-treated mice, which was partly attributable to blockade of transforming growth factor-beta signaling in dermal fibroblasts through the down-regulation of thrombospondin 1, a latent transforming growth factor-beta receptor, and transcription factors Smad3 and Ets1. Furthermore, bleomycin-dependent induction of T helper type 2-skewed immune polarization, M2 macrophage infiltration, and endothelial-to-mesenchymal transition were greatly suppressed in mice administered glycyrrhizin. Glycyrrhizin also improved vascular permeability of endothelial cell-specific Fli1-knockout mice by increasing the expression of molecules regulating vascular integrity. The authors concluded that glycyrrhizin ameliorates bleomycin-induced dermal fibrosis through the inhibition of fibroblast activation, T helper type 2-skewed immune polarization, M2 macrophage infiltration, endothelial-to-mesenchymal transition, and improves endothelial Fli1 deficiency-dependent vascular disintegrity. This suggests that glycyrrhizin may be a disease-modifying drug for SSc (3).

Wouldn’t that be sweet?

1. Aringer M, Erler A. Recent advance in managing systemic sclerosis. F1000Res 2017
2. Dastagir G, Rizvi MA. Review – glycyrrhiza glabra L. (Licquorice). Pak J Pharm Sci 2016; 29: 1727-33.
3. Yamashita T, et al. Glycyrrhizin ameliorates fibrosis, vasculopathy, and inflammation in animal models of systemic sclerosis. J Invest Dermatol 2017; 137: 631-40.

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