Skin Sclerosis In Patients Research Articles

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

Tissue injury/hypoxia and oxidative stress induced-extracellular adenosine triphosphate (ATP) can act as damage-associated molecular pattern molecules, which initiate inflammatory response. Our objective was to elucidate the role of extracellular ATP in skin fibrosis in systemic sclerosis (SSc). We identified that hypoxia enhanced ATP release and that extracellular ATP enhanced IL-6 production more significantly in SSc fibroblasts than in normal fibroblasts. There were no significant differences of P2X and P2Y receptor expression levels between normal and SSc fibroblasts. Nonselective P2 receptor antagonist and selective P2Y2 receptor antagonists, kaempferol and AR-C118925XX, significantly inhibited ATP-induced IL-6 production and phosphorylation of p38 in SSc fibroblasts. ATP-induced IL-6 production was significantly inhibited by p38 inhibitors, SB203580, and doramapimod. Collagen type I production in SSc fibroblasts by ATP-induced IL-6/IL-6 receptor trans-signaling was inhibited by kaempferol and SB203580. The amount of ATP in bleomycin-treated skin was increased, and administration of AR-C118925XX significantly inhibited bleomycin-induced dermal fibrosis in mice. These results suggest that vasculopathy-induced hypoxia and oxidative stress might enhance ATP release in the dermis in SSc and that extracellular ATP-induced phosphorylation of p38 via P2Y2 receptor might enhance IL-6 and collagen type I production in SSc fibroblasts. P2Y2 receptor antagonist therapy could be a treatment for skin sclerosis in patients with SSc.

Long-term follow-up of finger passive range of motion in Japanese systemic sclerosis patients treated with self-administered stretching

Objective: Severe skin sclerosis in patients with systemic sclerosis (SSc) can result in a loss of hand function. The aim of this study is to examine the long-term changes of finger passive range of motion (ROM) in Japanese SSc patients treated with self-administered stretching.Methods: This is a single-center, retrospective, observational cohort study. Forty-three Japanese patients with SSc were given instructions on self-administered stretching. ROM was assessed using a goniometer on their first visit and after 1 year, 3 years, 5 years and 9 years. Hand function was assessed by the Health Assessment Questionnaire disability index (HAQ-DI) at their first visit and after 9 years.Results: Total passive ROM significantly improved in each finger after 3 years of finger stretching. Most patients (37 of 43 patients, 86%) improved or maintained total passive ROM and hand function within 9 years after their first visit. However, significant improvement of total passive ROM was lost in 6 of 43 SSc patients (14%) 9 years after their first visit. The HAQ-DI also was increased in these six patients. Multivariable analyses revealed that re-elevation of modified Rodnan total skin thickness score during the clinical course (OR = 5.260e + 7, 95% CI 1.52e + 150–uncalculated p = .0096) was the independent factor associated with deterioration of total passive ROM at 9 years.Conclusion: Patients with progressive skin sclerosis during the clinical course need multimodality therapy to maintain finger joint motion, since the effect of self-administered stretching is limited in these patients.

Serum periostin levels are correlated with progressive skin sclerosis in patients with systemic sclerosis

Periostin, a matricellular protein, serves as a regulator of wound healing and fibrosis. The role of periostin in the pathogenesis of systemic sclerosis (SSc) is unknown. To determine periostin levels in association with severity of skin fibrosis in patients with SSc. Expression of periostin was immunohistochemically examined in skin obtained from patients with SSc and healthy controls. Enzyme-linked immunosorbent assay was performed to evaluate serum periostin levels in association with clinical characteristics in 56 patients with SSc [diffuse cutaneous SSc (dSSc), n=16; and limited cutaneous SSc (lSSc), n=40] and 66 healthy controls. Periostin was strongly expressed in the affected dermis from patients with SSc. Periostin was colocalized in α-smooth muscle actin-positive myofibroblasts and platelet endothelial cell adhesion molecule-1-positive endothelial cells in SSc dermis. Serum levels of periostin in patients with dSSc were markedly elevated compared with those in patients with lSSc and control subjects. Patients with lSSc had increased periostin levels compared with healthy controls. In addition, significantly higher levels of periostin were observed in patients with dSSc with disease duration ≤5 years compared with those with disease duration >5 years. Furthermore, the modified Rodnan total skin thickness score (MRSS) was positively correlated with periostin levels in patients with SSc. Serial analysis revealed a correlation between periostin and MRSS; namely, MRSS decreased in line with decreased periostin levels in some patients with dSSc as the disease progressed. An elevated periostin level in patients with SSc is associated with severity of skin sclerosis. Periostin may be a potential biomarker for progressive skin fibrosis in SSc.

A possible contribution of visfatin to the resolution of skin sclerosis in patients with diffuse cutaneous systemic sclerosis via a direct anti-fibrotic effect on dermal fibroblasts and Th1 polarization of the immune response

Visfatin is a member of the adipocytokines with pro-fibrotic, pro-inflammatory and immunomodulating properties potentially implicated in the pathogenesis of certain fibrotic and inflammatory autoimmune diseases. In this study, we investigated THE CLINICAL SIGNIFICANCE OF SERUM VISFATIN LEVELS AND ITS CONTRIBUTION TO THE DEVELOPMENTAL PROCESS IN SSC. Serum visfatin levels were determined by a specific ELISA in 57 SSc patients and 19 healthy controls. The mRNA levels of target genes were determined in normal and SSc fibroblasts by real-time RT-PCR. The levels of IL-12p70 produced by THP-1 cells were measured by a specific ELISA. Serum visfatin levels were comparable among total SSc, diffuse cutaneous SSc (dcSSc), limited cutaneous SSc and healthy controls. The only finding in a series of analyses regarding the correlation of serum visfatin levels with clinical symptoms and laboratory data was the significantly longer disease duration in dcSSc with elevated serum visfatin levels than in those with normal levels. Consistently, serum visfatin levels were significantly elevated in late-stage dcSSc (disease duration >6 years), but not in early and mid-stage dcSSc compared with healthy controls. In in vitro experiments, visfatin reversed the pro-fibrotic phenotype of SSc dermal fibroblasts and induced the expression of IL-12p70 in THP-1 cells treated with IFN-γ plus lipopolysaccharide. Visfatin may contribute to the resolution of skin sclerosis in late-stage dcSSc via a direct anti-fibrotic effect on dermal fibroblasts and Th1 polarization of the immune response.

Anti‐topoisomerase I antibody levels as serum markers of skin sclerosis in systemic sclerosis

The aim of the present study was to clarify the clinical significance of anti-topoisomerase I antibody (Ab) levels in Japanese patients with systemic sclerosis (SSc). Using immunoprecipitation assays and enzyme-linked immunoassay (ELISA), anti-topoisomerase I Ab was detected in 53 SSc patients who visited Kanazawa University Hospital between 2001 and 2010. In these patients, the association between serum anti-topoisomerase I Ab levels measured with ELISA and clinical features were compared using univariate analysis and multiple regression analysis. There were significantly positive correlations between anti-topoisomerase I Ab levels and the modified Rodnan total skin thickness score (MRSS) and skin thickness progression rate, and a significantly negative correlation with disease duration. On the other hand, anti-topoisomerase I Ab levels were not significantly associated with other clinical features including lung involvement. In a longitudinal study, anti-topoisomerase I Ab levels were decreased significantly in patients that had decreased MRSS, but not in patients that had unchanged or increased MRSS. There was a significantly positive association between anti-topoisomerase I Ab levels and MRSS and a significantly negative association with disease duration by multiple regression analysis. Our findings suggest that serum levels of anti-topoisomerase I Ab reflect the severity of skin sclerosis in patients with SSc.

Serum adiponectin levels inversely correlate with the activity of progressive skin sclerosis in patients with diffuse cutaneous systemic sclerosis

Adiponectin has been demonstrated to be one of anti-inflammatory and anti-fibrotic factors, suggesting the potential of this cytokine to be involved in the developmental process of systemic sclerosis (SSc). The aim of this study was to investigate the clinical significance of serum adiponectin levels in patients with SSc. Methods Serum adiponectin levels were determined using enzyme-linked immunosorbent assay (ELISA) in 32 patients with diffuse cutaneous SSc (dcSSc), 28 with limited cutaneous SSc (lcSSc) and 27 healthy controls. No significant difference between these groups existed in terms of gender, age and body mass index. Serum adiponectin levels in dcSSc patients (4.93 ± 6.48 μg/mL) were significantly lower than those in lcSSc patients (9.69 ± 7.61 μg/mL, P < 0.01) and healthy controls (9.36 ± 5.57 μg/mL, P < 0.01). dcSSc patients with disease duration of ≤5 years had significantly decreased serum adiponectin levels (2.15 ± 1.69 μg/mL) than those with disease duration of >5 years (13.29 ± 8.36 μg/mL, P < 0.01), lcSSc patients with disease duration of ≤5 years (8.07 ± 7.98 μg/mL, P < 0.05), lcSSc patients with disease duration of >5 years (10.9 ± 7.34 μg/mL, P < 0.01) and healthy controls (9.36 ± 5.57 μg/mL, P < 0.01). Longitudinal studies in five patients with early dcSSc treated with oral prednisone demonstrated that serum adiponectin levels inversely correlate with the activity of progressive skin sclerosis in dcSSc patients. Serum levels of adiponectin may serve as a useful marker to evaluate the activity of progressive skin sclerosis in dcSSc.

Serum CXCL16 Concentrations Correlate with the Extent of Skin Sclerosis in Patients with Systemic Sclerosis

To determine serum concentrations of soluble CXCL16 and its clinical associations in patients with systemic sclerosis (SSc). Serum CXCL16 levels from 89 patients with SSc were examined by ELISA. In a retrospective longitudinal study, 68 sera from 28 patients with SSc were analyzed (followup 1.3 to 7.3 yrs). Serum CXCL16 levels were elevated in patients with SSc compared with healthy controls (n = 42). Patients with diffuse cutaneous SSc (n = 52) had higher levels of CXCL16 than those with limited cutaneous SSc (n = 37). Serum CXCL16 levels correlated positively with the extent of skin sclerosis. In the longitudinal study, CXCL16 levels generally decreased on a parallel with the improvement in skin sclerosis. CXCL16 levels were increased in patients with SSc, and correlated with the extent of skin sclerosis, suggesting that CXCL16 may have a role in the development of skin fibrosis in SSc. Blockade of CXCL16 interaction might be a potential therapeutic target in patients with SSc.

Acute exacerbation of systemic scleroderma in Borrelia burgdorferi infection

In recent years a possible aetiological connection between skin sclerosis and an infection with Borrelia burgdorferi has been discussed, but this association has not yet been reported for systemic scleroderma. Several treatment modalities are suggested for systemic scleroderma, but no treatment has yet been found to alter the overall course of the disease. This report describes a 61-year-old woman with Raynaud's phenomenon, nail-fold changes and circulating anticentromere antibodies, who showed an abrupt onset of erythemas and doughy swellings involving the face and upper trunk, followed by thickening and induration of the skin mimicking diffuse systemic scleroderma. Laboratory tests including enzyme-linked immunosorbent assay (ELISA), immunoblot and urine polymerase chain reaction (PCR) showed an infection with B. burgdorferi sensu lato that was successfully treated with intravenous ceftriaxone, an antibiotic recommended for Lyme borreliosis. Fourteen days after the end of treatment the skin was no longer stiff and indurated and had returned to its normal predisease state. This case suggests that Lyme disease should be considered in atypical cases of skin sclerosis in patients predisposed to the development of systemic scleroderma.

Serum levels of tissue inhibitor of metalloproteinases 2 in patients with systemic sclerosis

Background: The serum tissue inhibitor of metalloproteinases 1 (TIMP-1) level was reported to be a useful indicator of disease activity, especially of lung fibrosis in patients with systemic sclerosis. TIMP-2 is also an important inhibitor of matrix metalloproteinases (MMPs), such as interstitial collagenase, gelatinase, and stromelysin, which control the metabolism of the extracellular matrix. However, serum levels of TIMP-2 in patients with systemic sclerosis (SSc) have not been investigated. Objective: We sought to determine the clinical significance of serum levels of TIMP-2 and MMP-2 in patients with SSc. Methods: Serum samples were obtained from 128 patients with SSc (68 with limited cutaneous SSc and 60 with diffuse cutaneous SSc). Twenty-seven serum samples from healthy age- and sex-matched individuals were also examined as controls. The TIMP-2 and MMP-2 levels were determined by means of sandwich enzyme-linked immunosorbent assays. Results: The serum TIMP-2 levels were elevated in 29 (22.7%) of the 128 patients with SSc and were significantly higher than those of the healthy control subjects. The serum TIMP-2 levels were significantly correlated with the extent of skin sclerosis in the patients with SSc. The incidence of decreased percentage of the diffusing capacity of lung for carbon monoxide (DLCO ) and that of an elevated erythrocyte sedimentation rate were significantly greater in the patients with elevated TIMP-2 levels compared with the patients with normal TIMP-2 levels (P < .05). When these patients were classified into 2 groups by disease activity, TIMP-2 levels were significantly more elevated in the high active group than in those low active group (P < .001). The serum MMP-2 levels of the patients with SSc were not significantly higher than those of the healthy control subjects. Conclusion: These findings suggest that the serum TIMP-2 level is a useful marker of the extent of skin sclerosis and disease activity in patients with SSc. The balance of TIMP-2 and MMP-2 may play an important role in patients with SSc. Furthermore, TIMP-2 may be thought to contribute to the development of disease in patients with SSc. (J Am Acad Dermatol 2000;42:70-5.)