Elevated MMP-7 levels in patients with systemic sclerosis: correlation with pulmonary involvement

Background: Fibrosis is characterized by an excessive accumulation of connective tissue because of an imbalance between synthesis and degradation of extracellular matrix proteins. Systemic sclerosis (SSc) is a prototypic chronic inflammatory disease leading to a severe fibrosis of the skin and many internal organs. Questions Addressed: We investigated whether serum MMP‐7 levels reflect the activity of the fibrotic reaction in systemic sclerosis. Experimental Design: Serum samples were obtained from 123 patients with systemic sclerosis. MMP‐serum levels of all patients with SSc were compared with age‐matched healthy controls. Results: Significantly increased median serum MMP‐7 levels were found in patients with SSc when compared with controls. The median MMP‐7 serum level of patients with lung fibrosis (LF) was significantly higher compared with those without LF. Accordingly, patients with dyspnea and DLCO (diffusion capacity of the lung for carbon monoxide) levels below 60% showed significantly higher median MMP‐7 levels. Conclusions: Elevated MMP‐7 levels are associated with an advanced stage of SSc and LF. These data suggest that in SSc MMP‐7 is involved in the process of fibrotic tissue remodelling.     

Serum aminoterminal propeptide of type III procollagen in systemic sclerosis. A follow-up--investigations in subclasses and during therapy.

Fifty-seven patients with systemic sclerosis were investigated for connective tissue turn-over related to type III collagen. Sera from 13 patients with diffuse cutaneous systemic sclerosis and 44 patients with limited cutaneous systemic sclerosis were analysed for aminoterminal propeptide of type III procollagen (PIIINP) by a radioimmunoassay based on human propeptide. Increased levels of PIIINP in serum correlated with skin involvement and the clinical course. All patients with diffuse cutaneous systemic sclerosis had levels above the normal range, and in limited cutaneous systemic sclerosis elevated PIIINP levels seemed to be correlated with rapid progression and with extension of lesions. Immunosuppressive drugs, cyclosporin A, and prednisone with or without cyclophosphamide, which were given to patients with rapid disease progression, significantly reduced PIIINP. This was also the case with penicillamine, but to a lesser degree. Our data support the suggestion that immunosuppressive agents are justified in rapidly progressive, life-threatening or disabling disease, when used with the necessary precautions. Serum PIIINP may be utilized as a marker of type III collagen fibrogenesis in systemic sclerosis and be of prognostic value. PIIINP may also be of use in the differential diagnosis between diffuse cutaneous systemic sclerosis and scleredema.     

Clinical significance of serum soluble T‐cell immunoglobulin and mucin domain 3 levels in systemic sclerosis: Association with disease severity

T‐cell immunoglobulin and mucin domain 3 (TIM‐3) has been thought to play a crucial role in the negative regulation of immune responses. Here, we examined the levels of serum soluble TIM‐3 (sTIM‐3) in patients with systemic sclerosis (SSc) and evaluated the results with respect to the clinical features of the disease. Patients with diffuse cutaneous SSc (dcSSc) had higher levels of sTIM‐3 than those with limited cutaneous SSc and healthy individuals. Serum sTIM‐3 levels were positively correlated with the severity of skin sclerosis in early phase dcSSc. Moreover, serum sTIM‐3 levels were increased more often in patients with renal crisis and cardiac involvement than in those with normal sTIM‐3 levels. These results suggest that serum sTIM‐3 levels may be increased in patients with early phase dcSSc and associated with cardiac involvement and renal crisis. Measurement of serum sTIM‐3 may be useful for risk stratification in the early stage of the disease.     

Serum levels of soluble programmed death‐1 and programmed death ligand‐1 in systemic sclerosis: Association with extent of skin sclerosis

The interaction of programmed death‐1 (PD‐1) with its ligand, programmed death ligand‐1 (PD‐L1), has been considered to play a key role in the negative regulation of immune responses. Patients with diffuse cutaneous systemic sclerosis (SSc) had higher levels of soluble PD‐1 (sPD‐1) than those with limited cutaneous SSc and healthy individuals. Serum sPD‐1 levels positively correlated with the severity of skin sclerosis. In contrast, serum sPD‐L1 levels were significantly increased in patients with SSc compared with healthy individuals. Moreover, serum sPD‐L1 levels were not associated with the extent of skin sclerosis and were elevated not only in patients with diffuse cutaneous SSc, but also in those with limited cutaneous SSc. These results suggested that serum sPD‐1 levels may increase in patients with SSc and correlate with the severity of skin sclerosis. PD‐1/PD‐L1 interaction may contribute to the development of skin sclerosis in SSc.     

Idiopathic and L-tryptophan-associated eosinophilic fasciitis before and after L-tryptophan contamination

Recently, a causative association has been made between the ingestion of levotryptophan (L-tryptophan) and the eosinophilia-myalgia syndrome (EMS), a new entity manifested by peripheral blood eosinophilia, myalgias, constitutional symptoms, and cutaneous edema with fibrosis. Contaminated levotryptophan preparations produced at a single manufacturing company between October 1988 and June 1989 have been implicated in all EMS cases. In this study, we analyzed retrospectively 49 patients with cutaneous fibrosis for a history of levotryptophan use. Levotryptophan ingestion prior to the onset of their disease was reported by 11 (65%) of 17 patients with eosinophilic fascilitis (EF), two (20%) of 10 patients with localized scleroderma, and none of 22 patients with systemic sclerosis. The onset of levotryptophan-associated cutaneous disease preceded the availability of contaminated levotryptophan preparations in seven (54%) of 13 patients. One patient with levotryptophan-associated generalized morphea also had lichen sclerosus et atrophicus and acanthosis nigricans, findings not previously reported in patients with EMS. In addition, we compared the clinical and laboratory features of levotryptophan-associated EF and idiopathic EF. Myalgias, muscle weakness, paresthesias, morpheaform plaques, cutaneous ulcers, and livedo reticularis were more common in patients with levotryptophan-associated EF. We conclude that levotryptophan-associated EF and localized scleroderma were present before the presumed date of contaminated levotryptophan availability. The clinical spectrum of cutaneous fibrosis associated with the ingestion of levotryptophan includes generalized morphea and EF, which are similar though not identical to their idiopathic counterparts.     

Serum levels of interleukin‐18‐binding protein isoform a: Clinical association with inflammation and pulmonary hypertension in systemic sclerosis

Systemic sclerosis (SSc) is a chronic autoimmune inflammatory disease characterized by extensive tissue fibrosis and various vascular complications. A wealth of evidence suggests the substantial contribution of pro‐inflammatory cytokines to the development of SSc, but the role of interleukin (IL)‐18 signaling in this disease still remains elusive. To address this issue, we herein determined serum levels of IL‐18‐binding protein isoform a (IL‐18BPa), a soluble decoy receptor for IL‐18, by enzyme‐linked immunosorbent assay in 57 SSc patients and 20 healthy controls and evaluated their clinical correlation. Serum IL‐18BPa levels were higher in SSc patients than in healthy controls, while comparable between diffuse cutaneous SSc and limited cutaneous SSc patients. Although serum IL‐18BPa levels were not associated with dermal and pulmonary fibrotic parameters in SSc patients, there was a significant positive correlation between serum IL‐18BPa levels and right ventricular systolic pressure estimated by echocardiography. Furthermore, in 24 SSc patients who underwent right heart catheterization, serum IL‐18BPa levels positively correlated with mean pulmonary arterial pressure. As for systemic inflammatory markers, significant positive correlations of circulating IL‐18BPa levels with erythrocyte sedimentation rate and C‐reactive protein were noted. These results suggest that the inhibition of IL‐18 signaling by IL‐18BPa may be involved in the development of pulmonary vascular involvement leading to pulmonary hypertension and modulate the systemic inflammation in SSc.     

Serum heparanase levels: A protective marker against digital ulcers in patients with systemic sclerosis

Heparanase is an endo‐β‐D‐glucuronidase cleaving heparan sulfate side‐chains of heparin sulfate proteoglycans, which is involved in wound healing, inflammation, neovascularization and tumor progression through the degradation and remodeling of the extracellular matrix and the release of sequestered pro‐angiogenic factors. Because heparanase‐mediated biological processes seem to be involved in the development of systemic sclerosis (SSc), we investigated the clinical correlation of serum heparanase levels in patients with this disease. Serum heparanase levels were significantly higher in SSc patients than in healthy individuals, while comparable between diffuse cutaneous SSc and limited cutaneous SSc subgroups. On the other hand, SSc patients with digital ulcers had serum heparanase levels significantly lower than those without. These results suggest that serum heparanase levels may be elevated in SSc patients reflecting the contribution of heparanase‐dependent biological processes to the development of SSc. SSc patients with high serum heparanase levels may be protected from the development of digital ulcers due to the increased release of sequestered pro‐angiogenic factors such as vascular endothelial growth factor. Therefore, serum heparanase levels may serve as a protective marker against digital ulcers in SSc patients.     

Serum interleukin‐34 levels in patients with systemic sclerosis: Clinical association with interstitial lung disease

Interleukin (IL)‐34 is a hematopoietic cytokine promoting proliferation and differentiation of macrophages. Because abnormal activation of macrophages is involved in the development of systemic sclerosis (SSc), we investigated serum IL‐34 levels in patients with SSc. Serum IL‐34 levels were significantly increased in diffuse cutaneous SSc compared with limited cutaneous SSc and healthy controls, while there were no significant differences between limited cutaneous SSc and healthy controls. In addition, SSc patients with increased serum IL‐34 levels more often had interstitial lung disease (ILD) than those with normal levels. Moreover, in SSc patients, serum IL‐34 levels negatively correlated with the percentage of predicted vital capacity, while they positively correlated with ground‐glass opacity score and fibrotic score on chest computed tomography. Collectively, increased serum IL‐34 levels were associated with greater frequency and severity of ILD in SSc patients. Serum IL‐34 levels may be a useful serological marker for SSc‐associated ILD.     

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 omentin levels: A possible contribution to vascular involvement in patients with systemic sclerosis

Adipokines have been shown to be potentially involved in various pathological processes of systemic sclerosis (SSc), including inflammation, vasculopathy and fibrosis, through their pleiotropic effects. Omentin is a member of the adipokines, and has a protective effect against vascular inflammation and pathological remodeling leading to atherosclerosis as well as a vasodilatory effect. To assess the potential role of omentin in the development of SSc, we determined serum omentin levels by enzyme‐linked immunosorbent assay in 66 SSc and 21 control subjects and evaluated their clinical correlation. Serum omentin levels were significantly decreased in diffuse cutaneous SSc patients compared with limited cutaneous SSc patients, while comparable between total SSc patients and healthy controls. In diffuse cutaneous (dc)SSc, patients with a disease duration of 5 years or less had serum omentin levels significantly lower than those with a disease duration of more than 5 years. In total SSc, serum omentin levels were significantly higher in patients with elevated right ventricular systolic pressure than in the others, while serum omentin levels did not correlate with fibrotic and systemic inflammatory parameters. These results suggest that a loss of omentin‐dependent protection against vascular inflammation and remodeling may be related to pathological vascular events of early dcSSc. The elevation of serum omentin levels may serve as a marker of vascular involvement leading to pulmonary arterial hypertension in SSc, which is possibly due to the compensatory induction of omentin against the increased pulmonary vascular tone.     

Clinical significance of serum soluble Tie1 levels in patients with systemic sclerosis

Tie1 is an endothelial cell-specific tyrosine kinase receptor, which maintains vascular integrity and regulates angiogenesis via modulating angiopoietin/Tie2 signaling. Since the altered angiogenesis is closely related to the developmental process of systemic sclerosis (SSc), we herein investigated the clinical significance of serum soluble Tie1 (sTie1) levels and the expression levels of Tie1 in dermal microvascular endothelial cells (DMECs) in patients with SSc. Although serum sTie1 levels were comparable among total SSc, diffuse cutaneous SSc (dcSSc), limited cutaneous SSc (lcSSc), and healthy controls, SSc patients with decreased serum sTie1 levels had significantly shorter disease duration than those with serum sTie1 levels not decreased. In SSc patients with disease duration of >6 years, the prevalence of clinical symptoms associated with proliferative vasculopathy, such as digital ulcers, scleroderma renal crisis, and elevated right ventricular systolic pressure, was significantly higher in patients with decreased serum sTie1 levels than in those with serum sTie1 levels not decreased. In immunohistochemistry, Tie1 expression was reduced in DMECs of SSc patients with disease duration of <3 years compared with those of healthy controls. Collectively, in SSc patients with short disease duration, decreased serum sTie1 levels may reflect the down-regulation of Tie1 in DMECs. The decrease in serum sTie1 levels may serve as a marker of proliferative vasculopathy in SSc with disease duration of >6 years.     

Possible association of decreased serum CXCL14 levels with digital ulcers in patients with systemic sclerosis

CXCL14 serves as a chemoattractant for activated macrophages, immature dendritic cells and natural killer cells, as well as an antiangiogenic factor by preventing the migration of endothelial cells. CXCL14 also exerts an inhibitory effect on the CXCL12/CXCR4 signaling pathway, which is involved in the maintenance of T‐helper (Th)2 bias, and promotes Th1 immune response under the physiological and pathological conditions. Because CXCL14‐mediated biological processes seem to be involved in the development of systemic sclerosis (SSc), which is characterized by Th2/Th17‐skewed immune polarization and impaired neovascularization, we investigated the clinical correlation of serum CXCL14 levels in patients with this disease. Serum CXCL14 levels were significantly decreased in SSc patients compared with healthy individuals and in diffuse cutaneous SSc patients relative to limited cutaneous SSc patients. SSc patients with digital ulcers had serum CXCL14 levels significantly lower than those without. Furthermore, i.v. cyclophosphamide pulse significantly increased serum CXCL14 levels as compared with the baseline in SSc patients with interstitial lung disease successfully treated with this therapy. These results indicate that decreased CXCL14 expression may contribute to the maintenance of Th2‐skewed immune polarization and dysregulated neovascularization, both of which underlie the developmental process of SSc.     

Clinical significance of serum decoy receptor 3 levels in patients with systemic sclerosis

Decoy receptor 3 (DcR3) is associated with autoimmunity and altered angiogenesis in certain pathological conditions. We herein measured serum DcR3 levels in 51 patients with systemic sclerosis (SSc) and 19 healthy controls and evaluated their clinical significance in this disorder. Serum DcR3 levels were significantly higher in diffuse cutaneous SSc (dcSSc) patients than in limited cutaneous SSc patients and in healthy controls. In dcSSc, serum DcR3 levels were significantly elevated in patients with disease duration of ≤6?years compared with healthy controls, but not in those with disease duration of >6?years. Serum DcR3 levels correlated negatively with the percentage of predicted diffusion lung capacity for carbon monoxide and positively with right ventricular systolic pressure. Furthermore, serum DcR3 levels positively correlated with C-reactive protein, erythrocyte sedimentation rate and immunoglobulin G. Collectively, the elevation of serum DcR3 levels is associated with the development of pulmonary arterial hypertension and systemic inflammation in SSc.     

Clinical significance of serum retinol binding protein‐4 levels in patients with systemic sclerosis

Background Retinol binding protein‐4 (RBP‐4) is a member of adipocytokines, which is potentially associated with fibrosis, vasodilation, and angiogenesis in addition to insulin resistance. Objective To investigate the clinical significance of serum RBP4 levels in patients with systemic sclerosis (SSc), which is a systemic autoimmune disease characterized by fibrosis and vasculopathy. Methods Serum RBP4 levels were determined by enzyme‐linked immunosorbent assay in 62 SSc patients and 19 healthy controls. Results Similar to patients with chronic kidney disease, serum RBP4 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. Therefore, analyses were carried out by excluding SSc patients with estimated glomerular filtration rate <60 mL/min/1.73 m². Serum RBP4 levels were significantly lower in diffuse cutaneous SSc (dcSSc) than in control subjects [median (25–75 percentile); 25.8 μg/mL (19.6–47.0) vs. 43.1 μg/mL (31.7–53.4), P < 0.05], while there was no significant difference between limited cutaneous SSc (lcSSc) [28.0 μg/mL (25.4–43.3)] and control subjects. In both of dcSSc and lcSSc, patients with Raynaud’s phenomenon had RBP4 levels significantly lower than those without. Furthermore, serum RBP4 levels inversely correlated with pulmonary function test results in dcSSc and with right ventricular systolic pressure in lcSSc. Conclusion Decreased RBP4 levels are associated with the prevalence of Raynaud’s phenomenon in dcSSc and lcSSc, with the severity of interstitial lung disease in dcSSc, and with the degree of pulmonary vascular involvement in lcSSc, suggesting the possible contribution of RBP4 to the pathological events in this disorder.     

系统性硬化病与多发性肌炎重叠综合征50例分析

目的探讨系统性硬化病重叠多发性肌炎患者的临床特点和治疗反应,以提高对本病的认识和诊治水平。方法对本科1991～2008年就诊的系统性硬化病与多发性肌炎重叠综合征的50例患者的临床资料进行回顾性分析。结果50例患者中,女性42例(84.0%),平均发病年龄39.0±12.1岁,就诊时平均病程2.7±3.1年。全部患者出现雷诺现象、皮肤硬化,伴有不同程度的肌无力,主要累及四肢近端肌肉。皮肤硬化呈弥漫性者占54.0%,肢端型者占46.0%。血清肌酶谱检测升高者共44例(88.0%),升高频率依次为:α-羟丁酸脱氢酶74%、天门冬氨酸氨基转移酶72.0%、乳酸脱氢酶62.0%、肌酸激酶54.0%。抗核抗体阳性96.0%,抗Scl-70抗体阳性30.0%,抗着丝点抗体阳性4.0%,抗RNP阳性44.0%,仅1例抗Jo-1抗体阳性。治疗上采用小剂量糖皮质激素结合中药效果较好。结论系统性硬化病与多发性肌炎重叠综合征常累及多个系统器官,并存在多种免疫学异常。可采用小剂量糖皮质激素结合中药进行治疗。     

Serum levels of interleukin-6 and interleukin-10 correlate with total skin thickness score in patients with systemic sclerosis

Various growth factors and cytokines have been suggested to play a central role in initiating and developing fibrosis in systemic sclerosis (SSc). To determine which serum levels of soluble mediators are the most relevant to the degree of skin sclerosis in SSc, serum levels of various soluble mediators were examined by ELISA and correlated with skin thickening that was measured using modified Rodnan total skin thickness scoring (TSS) system. Serum levels of IL-4, IL-12, IL-13, tumor necrosis factor-alpha, connective tissue growth factor (CTGF), vascular endothelial growth factor, monocyte chemotactic protein-1, macrophage inflammatory protein-1beta, soluble IL-6 receptor, and soluble L-selectin were higher in SSc patients than normal controls. Levels of IL-6, IL-10, and CTGF in patients with diffuse cutaneous SSc were higher than patients with limited cutaneous SSc and controls. Serum levels of IL-6 and IL-10 positively correlated with TSS in patients with SSc (r=0.625, P<0.0001 and r=0.663, P<0.0001, respectively). In addition, IL-10 levels significantly correlated with pulmonary fibrosis. Thus, serum levels of IL-6 and IL-10 most strongly reflect the extent of skin thickening in SSc, suggesting that levels of IL-6 and IL-10 are useful serological indicators for skin fibrosis in SSc.     

Serum levels of ADAM12‐S: possible association with the initiation and progression of dermal fibrosis and interstitial lung disease in patients with systemic sclerosis

Background A disintegrin and metalloprotease (ADAM) 12 is one of the metalloproteinase‐type ADAMs and possesses extracellular metalloprotease and cell‐binding functions. ADAM12 is expressed in two alternative forms, such as a membrane‐anchored form (ADAM12‐L) and a short secreted form (ADAM12‐S). Objective To investigate the clinical significance of serum ADAM12‐S levels in systemic sclerosis (SSc). Methods Serum ADAM12‐S levels were determined by a specific enzyme‐linked immunosorbent assay in 61 SSc patients and 18 healthy controls. Results Serum ADAM12‐S levels were significantly increased in diffuse cutaneous SSc (dcSSc) patients than in healthy controls (0.417 ± 0.389 vs. 0.226 ± 0.065 ng/mL; P < 0.05), while being comparable between limited cutaneous SSc (0.282 ± 0.258 ng/mL) and healthy controls. Serum ADAM12‐S levels significantly elevated in dcSSc patients with disease duration of ≤6 years (0.537 ± 0.449 ng/mL, P < 0.05), but not in dcSSc with disease duration of >6 years (0.225 ± 0.049 ng/mL), compared to healthy controls. Furthermore, in dcSSc patients with disease duration of ≤6 years, serum ADAM12‐S levels correlated positively with modified Rodnan total skin thickness score, ground glass score, and serum C‐reactive protein values, while showed inverse correlation with fibrosis score. Conclusion Elevated serum ADAM12‐S levels are associated with elevated serum inflammatory marker, severity of skin fibrosis, and activity of interstitial lung disease in dcSSc, suggesting the possible contribution of ADAM12‐S to the pathological events in this disorder.     

Cutaneous lesions of dermatomyositis with supervening fibrosis

Background: Dermatomyositis (DM) is a distinctive systemic connective tissue disease whereby the skin defines a cardinal site of involvement. There exists a body of literature, which suggests that a significant component of its clinical manifestations may be related to endothelial cell injury. We have postulated in the past that anti‐endothelial cell antibodies may be the defining trigger leading to endothelial cell dysfunction. The primary organs affected by DM are the skin and muscle. A significant albeit rare complication is pulmonary fibrosis, which our recent study postulated to be attributable to an autoimmune endothelialitis. Design: We describe six patients, four women and two men who ranged in age from 3 to 60 years, and had classic clinical presentations and cutaneous lesions of DM without any supervening clinical changes indicative of cutaneous sclerosis. Results: Skin biopsies showed cell‐poor interface dermatitis with variable dermal mucin and C5b‐9 within the cutaneous vasculature. However, at variance with classic DM was the presence of a sclerodermoid tissue reaction, which was of variable depth. All of these patients had severe muscle involvement. One pediatric patient had concomitant significant cutaneous, central nervous system and oral mucosal ischemic infarcts. Significant pulmonary disease ensued in the four adult patients, manifesting as pulmonary fibrosis in two, diffuse alveolar damage in one and diaphragmatic failure in one. In three patients, direct immunofluorescent studies were corroborative of immune‐based microvascular injury while Western blot and/or indirect immunofluorescent studies showed anti‐endothelial cell antibody activity within the serum of three patients. Conclusions: The identification of sclerosis in biopsies of skin lesions typical clinically for DM may be a harbinger for more severe autoimmune‐based endothelial cell injury phenomenon. One could speculate that its basis may be attributable to elevated serum levels of the natural fibrogenic factor, transforming growth factor β, which in turn is released from damaged endothelium.     

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

Background 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. Objective To determine periostin levels in association with severity of skin fibrosis in patients with SSc. Methods 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. Results 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. Conclusion 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.     

CXCL13 produced by macrophages due to Fli1 deficiency may contribute to the development of tissue fibrosis,vasculopathy and immune activation in systemic sclerosis

CXCL13, a chemokine for B cells, follicular T cells, T helper 17 cells, and regulatory T cells, is reported to contribute to the development of systemic sclerosis (SSc), reflecting aberrant activation of immune system. To better understand the role of CXCL13 in SSc, we investigated the influence of Fli1 deficiency, a potential predisposing factor of this disease, on CXCL13 expression and assessed the clinical correlation of serum CXCL13 levels by multivariate regression analysis. Haploinsufficient loss of Fli1 remarkably induced CXCL13 expression in murine peritoneal macrophages, while gene silencing of FLI1 did not affect the expression of CXCL13 in human dermal fibroblasts and human dermal microvascular endothelial cells. Serum CXCL13 levels were elevated in SSc patients compared with healthy controls and correlated positively with skin score and negatively with pulmonary function test results. SSc patients with elevated serum CXCL13 levels had longer disease duration, diffuse cutaneous involvement, interstitial lung disease (ILD), heart involvement, pulmonary arterial hypertension, Raynaud's phenomenon, pitting scars, digital ulcers, telangiectasia, and high serum IgG levels more frequently than the other patients. In particular, serum CXCL13 levels were associated with ILD and digital ulcers by multivariate regression analysis. Taken together, these results indicate that CXCL13 expression is upregulated by Fli1 deficiency in macrophages, potentially contributing to the development of tissue fibrosis, vasculopathy and immune activation in SSc, especially ILD and digital ulcers.