Elevated plasma homocysteine level is possibly associated with skin sclerosis in a series of Japanese patients with systemic sclerosis

Abstract

Homocysteine is a sulfhydryl-containing amino acid that is derived from dietary methionine, and there has been increasing evidence that elevated plasma homocysteine levels are associated with increased risk of cardiovascular diseases, including carotid, coronary and peripheral arterial disease (PAD). The association of plasma homocysteine levels with peripheral vascular involvements, such as Raynaud phenomenon (RP), digital ulcers (DU) in systemic sclerosis (SSc) patients has not been well studied. The objective of this study was to examine plasma homocysteine levels and their clinical associations in patients with SSc. Plasma homocysteine levels in 151 Japanese patients with SSc and 20 healthy controls were examined. No significant differences were observed in plasma homocysteine levels between SSc patients and healthy individuals. Demographic and clinical features of the SSc patients revealed that severe skin sclerosis, anti-topoisomerase I antibody positivity, complications of DU, acro-osteolysis (AO) and interstitial lung disease (ILD) were significantly more prevalent among the patients with elevated plasma homocysteine levels. The plasma homocysteine levels were positively correlated with modified Rodnan total skin score. The plasma homocysteine levels in the SSc patients with DU, AO and ILD were significantly higher than those in the SSc without DU, AO and ILD, respectively. Plasma homocysteine levels did not correlate with either the mean or max intima-media thickness (IMT) or plaque score, suggesting that plasma homocysteine levels might not be associated with carotid artery atherosclerosis in SSc patients. The measurement of plasma homocysteine levels in SSc patients might be useful for the risk stratifications of severe skin sclerosis, DU and AO.

Inhibitory effect of kaempferol on skin fibrosis in systemic sclerosis by the suppression of oxidative stress

“…There are many previous reports which demonstrated that the serum levels of oxidative stress-related factors, such as nitric oxide, Abbreviations: ATP, adenosine triphosphate; ECs, endothelial cells; HO-1, Heme Oxygenase 1; IL-6, interleukin-6; Nox, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; Nrf2, NF-E2-related factor 2; ROS, reactive oxygen species; SSc, systemic sclerosis; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; Trx2, thioredoxin 2; TUNEL, terminal deoxynucleotide transferase dUTP nick end-labeling. malondialdehyde, asymmetric dimethylarginine, hydroperoxide, and homocysteine, increased in patients with SSc [4,5]. Antioxidative biomarkers, such as superoxide dismutase and vitamin C, were lower in the serum of patients with SSc compared to healthy controls [4].…”

“…Almost all patients present Raynaud's phenomenon as an initial symptom, and frequently show other manifestations of vascular diseases, including ischemic digital ulcers, pulmonary arterial hypertension, and renal arterial involvement associated with malignant hypertension and renal failure. Although the pathogenesis of SSc remains unknown, it has been elucidated that vasculopathyinduced hypoxia and oxidative stress play an important role in the prognosis of SSc [3][4][5][6][7][8]. Vasculopathy in patients with SSc is characterized by the activation of endothelial cells (ECs) and altered vascular tone.…”

The Regulation of Skin Fibrosis in Systemic Sclerosis by Extracellular ATP via P2Y2 Purinergic Receptor

“…Hypoxia and oxidative stress are also induced by ischemia and reperfusion injury after Raynaud's phenomenon (Simonini et al, 2000;Uchiyama et al, 2015). Many previous studies have reported that serum levels of oxidative stress-related factors were enhanced in SSc patients (Luo et al, 2017;Motegi et al, 2014). In addition, mice treated with agents that induce the release of free radicals, such as hydroxyl radicals and peroxynitrites, exhibited cutaneous and lung fibrosis (Servettaz et al, 2009).…”

Possible association of elevated serum collagen type IV level with skin sclerosis in systemic sclerosis

“…Systemic sclerosis (SSc) is a connective tissue disease characterized by the fibrosis of the skin and internal organs, microangiopathy and autoimmunity . SSc patients develop various microangiopathies, such as Raynaud's phenomenon (RP), nail fold capillary abnormality, persistent digital ischemia, acro‐osteolysis (AO) and digital ulcers (DU) . RP and nail fold capillary abnormality generally precede the onset of fibrosis by several months or years, suggesting that vascular disorder may be a primary event in the pathogenesis of SSc .…”

“…[1][2][3][4] SSc patients develop various microangiopathies, such as Raynaud's phenomenon (RP), nail fold capillary abnormality, persistent digital ischemia, acro-osteolysis (AO) and digital ulcers (DU). 2,3,[5][6][7] RP and nail fold capillary abnormality generally precede the onset of fibrosis by several months or years, suggesting that vascular disorder may be a primary event in the pathogenesis of SSc. 2,3 Increasing evidence suggests that injury and damage of microvascular endothelial cells (EC) may occur in early SSc, leading to the proliferation of the intima, vessel narrowing and obliteration.…”