Serum levels of tenascin‐C in collagen diseases

Tenascins are a family of large multimetric extracellular matrix (ECM) proteins. Among them, large molecular weight variant tenascin‐C is known to be specifically expressed in pathological conditions. However, no link between tenascin‐C and collagen diseases has been established. The aim of our study was to determine the serum tenascin‐C levels in patients with various collagen diseases, and to evaluate the possibility that serum levels of tenascin‐C can be a useful marker for collagen diseases, correlating with the pathogenesis. Serum tenascin‐C levels of 33 patients with scleroderma (SSc), 10 patients with scleroderma spectrum disorder (SSD), 15 patients with localized scleroderma (LSc), 12 patients with dermatomyositis (DM), 10 patients with systemic lupus erythematosus (SLE) and 15 healthy controls were measured with specific enzyme‐linked immunosorbent assays. Serum tenascin‐C levels were significantly elevated in patients with SSc, SSD and LSc than in healthy controls. Significantly higher total skin thickness score or higher incidence of pitting scars/ulcers and diffuse pigmentation were observed in SSc patients with elevated tenascin‐C levels than in those with normal levels. Our study suggests that serum tenascin‐C levels are increased in fibrotic conditions, and that tenascin‐C contributes to the pathogenesis of vascular damage as well as fibrosis in SSc patients. Clarifying the role of tenascin‐C in the pathogenesis of collagen diseases may lead to a new therapeutic approach.     

Serum angiopoietin-like protein 3 concentrations in rheumatic diseases

Angiopoietin-like protein 3 (Angptl3) is one of the angiogenic cytokines that stimulates endothelial cell adhesion, migration, and neovascularization. No link has been established between Angptl3 and rheumatic diseases such as systemic sclerosis or dermatomyositis (DM). In this study, we determined the serum Angptl3 levels in patients with various rheumatic diseases, and tried to evaluate the possibility that serum levels of Angptl3 can be a useful disease marker. Serum samples were collected from 21 SSc patients, 10 systemic lupus erythematosus (SLE) patients, 21 DM patients, 5 polymyositis (PM) patients and 11 patients with clinically amyopathic DM (CADM) as well as 12 healthy volunteers. Levels of serum Angptl3 were measured with a specific ELISA kit. There was a significant increase of serum Angptl3 levels in patients with SSc or DM (p<0.05). Levels of serum Angptl3 were also slightly higher in patients with ADM, PM or SLE compared with healthy controls, but not statistically significant. Myoglobin levels were significantly higher in DM patients with increased serum Angptl3 levels than those with normal levels (p<0.05). In addition, among patients with SSc, the prevalence of cutaneous ulcers was significantly greater in patients with elevated Angptl3 levels than those with normal levels (p<0.05). Serum Angptl3 levels may be associated with the pathogenesis of muscle involvement in DM patients and microangiopathy in SSc patients. Clarifying the role of Angptl3 in each rheumatic disease may lead to further understanding of the pathogenesis and new therapeutic approaches.     

Surfactant protein D (SP-D) and systemic scleroderma (SSc)

We measured serum levels of SP-D in collagen diseases (110 cases) such as systemic scleroderma (SSc), scleroderma spectrum disorders (SSD), systemic lupus erythematodes (SLE), Sjogren syndrome (Sjs), dermatomyositis (DM), rheumatoid arthritis (RA), and dermatitis (DE) (109 cases) as a control. Additionally, we performad a correlation analysis to determine how these levels were related to pulmonary fibrosis and function test (vital capacity, %DLco). The serum levels of SP-D increased in SSc patients with Barnett type III more than in SSc patients with Barnett type I or II, while they increased slightly in SSD (incomplete type of SSc) patients. The differences in these figures were statistically significant between the SSc (SSc & SSD) and non-SSc (SLE, DM, Sjs & RA) groups (p<0.005). The serum levels of SP-D in SSc patients with anti-topoisomerase I antibodies were statistically higher than those in SSc patients with other types of anti-nuclear antibodies. There was a statistically significant correlation between the severity of pulmonary fibrosis and the serum levels of SP-D, and a statistically negative correlation between SP-D levels and vital capacity or %DLco, but there was no proportional correlation with the forced expiatory volume (FEV1.0%). There was no statistical relationship between pre- and post-therapy with photopheresis; however, there was a statistical correlation between the serum levels of SPD and KL-6. In the group of collagen diseases, plasma levels of SP-D were higher than serum levels of SP-D. Patients with SSc possess higher levels of SP-D than do those with other collagen diseases and dermatitis, which may correspond to the severity of pulmonary fibrosis.     

CCL13 is a promising diagnostic marker for systemic sclerosis

Background Previous studies suggest that CCL13 may have some role in the pathogenesis of systemic sclerosis (SSc). Objectives To determine serum levels of CCL13 and its clinical associations in patients with SSc. Methods Serum CCL13 levels were examined by enzyme‐linked immunosorbent assay in 80 patients with SSc, 20 patients with systemic lupus erythematosus (SLE), 20 patients with dermatomyositis (DM), 29 patients with atopic dermatitis (AD) and 50 healthy individuals. Results Mean ± SD serum CCL13 levels were elevated in patients with SSc (81·3 ± 55·8 pg mL^?1) compared with healthy controls (15·0 ± 9·9 pg mL^?1; P < 0·001) and patients with SLE (22·0 ± 6·9 pg mL^?1; P < 0·001), DM (24·4 ± 36·1 pg mL^?1; P < 0·001) and AD (18·0 ± 6·4 pg mL^?1; P < 0·001). Among patients with SSc, there were no differences in serum CCL13 levels between limited cutaneous SSc and diffuse cutaneous SSc. In a longitudinal study, CCL13 levels were generally unchanged during the follow‐up. Conclusions Serum CCL13 was specifically increased in patients with SSc, but not in patients with SLE, DM or AD or in healthy controls. CCL13 could be a promising serological marker for SSc.     

Elevated serum BAFF levels in patients with localized scleroderma in contrast to other organ-specific autoimmune diseases

Serum levels of B-cell activating factor belonging to the tumor necrosis factor family (BAFF), a potent B-cell survival factor, are elevated in patients with systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis and systemic sclerosis (SSc). The objective of this study was to determine serum BAFF levels and relate the results to the clinical features in patients with organ-specific autoimmune diseases of the skin, such as localized scleroderma and autoimmune bullous diseases. Serum BAFF levels were examined by enzyme-linked immunosorbent assay in 44 patients with localized scleroderma, 20 with pemphigus vulgaris/pemphigus foliaceus, 20 with bullous pemphigoid and 30 healthy controls. Twenty patients with SSc and 20 with SLE were also examined as disease controls. Serum BAFF levels were elevated in localized scleroderma patients compared with healthy controls. Concerning localized scleroderma subgroups, patients with generalized morphea, the severest form of localized scleroderma, had higher serum BAFF levels than linear scleroderma or morphea patients. The BAFF levels of generalized morphea were comparable with those of SSc or SLE. Furthermore, serum BAFF levels correlated positively with antihistone antibody levels and the severity of skin lesion as well as the number of skin lesions. By contrast, serum BAFF levels were not significantly elevated in patients with pemphigus or pemphigoid. These results suggest that BAFF may be contributing to autoimmunity and disease development in localized scleroderma.     

Serum levels of a Th1 chemoattractant IP-10 and Th2 chemoattractants, TARC and MDC, are elevated in patients with systemic sclerosis

BACKGROUND: Although abnormalities of various chemokines are detected in systemic sclerosis (SSc), there are few findings concerning Th1 or Th2 chemoattractants. OBJECTIVE: To determine whether serum levels of chemokines preferentially chemotactic for Th1 cells (IP-10 and MIG) and predominantly chemotactic for Th2 cells (TARC and MDC) are elevated and whether they correlate with clinical features in patients with SSc. METHODS: Serum samples from patients with diffuse cutaneous SSc (dSSc; n = 34), limited cutaneous SSc (lSSc; n = 30), dermatomyositis (DM; n = 15), systemic lupus erythematosus (SLE; n = 22), and normal controls (n = 30) were examined by sandwich ELISA. RESULTS: Serum TARC levels were significantly elevated in dSSc patients (P < 0.0002) and lSSc patients (P < 0.0001) compared with normal controls. Similarly, serum MDC levels were significantly increased in patients with dSSc (P < 0.02) or lSSc (P < 0.05) relative to normal controls. In addition, serum IP-10 was detected significantly more frequently in patients with dSSc (44%), lSSc (30%), or DM (53%) than normal controls (0%) and patients with SLE (0%). Furthermore, elevated TARC levels correlated with the presence of pitting scars and anti-topoisomerase I antibody, increased titers of anti-topoisomerase I and antinuclear antibody, and decreased glomerular filtration rate. Increased MDC levels were associated with pitting scars and younger ages at onset. CONCLUSION: These results suggest that both Th2 chemoattractants, TARC and MDC, and a Th1 chemoattractant IP-10 play a role in the development of SSc.     

Successful experience of rituximab therapy for systemic sclerosis‐associated interstitial lung disease with concomitant systemic lupus erythematosus

Previous studies have demonstrated that B cells play critical roles in autoimmune disorders including systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). However, the effectiveness of rituximab (RTX), a chimeric anti‐CD20 antibody, for SSc‐associated interstitial lung disease (ILD) or SLE disease activity remains controversial. We herein report an SSc patient with severely progressed ILD and concomitant SLE treated by two cycles of RTX at baseline and half a year later. This treatment improved ILD and SLE activities, along with reduction of dermal sclerosis and serum anti‐topoisomerase I antibody levels. In addition, our detailed time‐course data indicate that half a year may be appropriate as an interval between each cycle of RTX therapy aimed at SSc‐associated ILD or SLE. Overall, the current report could pave the way to establish RTX as a disease‐modifying drug for patients with SSc and/or SLE showing resistance to other already approved medications.     

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.     

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.     

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.     

Elevated serum MFG‐E8 level is possibly associated with the presence of high‐intensity cerebral lesions on magnetic resonance imaging in patients with systemic lupus erythematosus

Human milk fat globule‐EGF factor 8 (MFG‐E8), also known as lactadherin, is a secreted glycoprotein that plays essential roles in the clearance of apoptotic cells and angiogenesis. It has been reported that serum MFG‐E8 levels are higher in systemic lupus erythematosus (SLE) patients compared with in healthy controls; however, a previous study reported no correlation between serum MFG‐E8 levels and SLE disease activity. The objective of this study was to assess serum MFG‐E8 levels and their clinical associations in patients with SLE. Serum MFG‐E8 levels in 49 Japanese patients with SLE, eight with cutaneous LE, and 28 healthy controls were examined. Serum MFG‐E8 levels in SLE patients were significantly higher than those in cutaneous LE patients and healthy individuals. In addition, serum MFG‐E8 levels were positively correlated with the SLE Disease Activity Index score, which reflects the disease activity of SLE. Notably, the frequency of the presence of high‐intensity cerebral lesions on MRI in the SLE patients with elevated serum MFG‐E8 levels was significantly higher than that in SLE patients with normal serum MFG‐E8 levels. These findings suggest that elevated serum MFG‐E8 levels may be associated with cerebrovascular diseases or neuropsychiatric SLE in patients with SLE, and that the measurement of serum MFG‐E8 levels in SLE patients is useful for risk stratification of cerebrovascular disease or cerebrovascular disease‐related neuropsychiatric SLE.     

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 levels of soluble vascular endothelial growth factor receptor‐2 in patients with systemic sclerosis

Background Although vascular endothelial growth factor (VEGF)‐A/VEGF receptor 2 (KDR) signalling may play a major role in the microangiopathy of systemic sclerosis (SSc), serum levels of soluble KDR (sKDR) in this disease have not yet been determined. Objectives To evaluate the possibility that serum sKDR levels can be a specific disease marker of SSc. Methods Serum sKDR levels of 42 patients with SSc, 10 patients with Raynaud’s phenomenon (RP) and 22 healthy controls were measured with specific enzyme‐linked immunosorbent assays. Quantitative real‐time polymerase chain reaction (PCR) was performed to determine KDR mRNA levels. Results In females, the serum sKDR levels were significantly higher in patients with SSc, especially limited cutaneous SSc, than in patients with RP or healthy controls. Quantitative real‐time PCR with RNA from skin sections revealed that KDR mRNA levels were also increased in the skin of patients with SSc with elevated serum sKDR levels. A significantly lower prevalence of pulmonary fibrosis, higher percentage vital capacity, and a higher incidence of telangiectasia were seen in female patients with SSc with elevated serum sKDR levels than those with normal levels. Conclusions These results suggest that the skin can be one of the sources of elevated serum sKDR levels, and that serum sKDR levels are useful for diagnosis and may be a marker of microangiopathy in patients with SSc, especially females. The VEGF‐A/KDR signalling system may be involved in the pathogenesis of the disease.     

Serum apelin levels: clinical association with vascular involvements in patients with systemic sclerosis

Background Apelin is a bioactive peptide exerting its pro‐angiogenic and pro‐fibrotic effects in a context‐dependent manner through the activation of its receptor APJ, which is ubiquitously expressed on the surface of various cell types. The activation of apelin/APJ signalling appears to be involved in the pathological process of fibrotic disorders, including liver cirrhosis. Objective As an initial step to clarify the role of apelin/APJ signalling in the pathogenesis of systemic sclerosis (SSc), we investigated serum apelin levels and their clinical association in patients with SSc. Methods Serum apelin levels were determined by a specific enzyme‐linked immunosorbent assay in 56 SSc patients and 18 healthy controls. Results Serum apelin levels were comparable among three groups, including diffuse cutaneous SSc, limited cutaneous SSc and control subjects (1.77 ± 1.48, 1.63 ± 1.51 and 1.61 ± 0.44 ng/mL, respectively). When we classified SSc patients into three groups according to disease duration, serum apelin levels were elevated in early SSc (<3 years) compared with mid‐stage SSc (3–10 years) (1.74 ± 1.26 vs. 1.02 ± 0.52 ng/mL, P < 0.05). Importantly, in late stage SSc (>10 years), the prevalence of severe vascular involvements, including intractable skin ulcers, scleroderma renal crisis and pulmonary arterial hypertension, was significantly higher in patients with elevated serum apelin levels than in those without (100% vs. 20%, P < 0.05). Conclusion Apelin may be associated with altered and activated angiogenesis prior to fibrotic responses in early SSc and with the development of proliferative vasculopathy in late stage 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.     

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 antinuclear matrix antibody in serum from patients with anti-U1RNP antibody

Abstract Serum containing anti-U1RNP antibodies reacts with the nuclear matrix, the relatively insoluble component of the cell nucleus, in addition to U1RNP. In this study, we determine the serum titer and clinical correlations of antinuclear matrix antibodies in samples from patients with anti-U1RNP antibodies. The patients with anti-U1RNP antibodies were classified as having mixed connective tissue disease (MCTD, 15 patients), systemic sclerosis (SSc, 12 patients), systemic lupus erythematosus (SLE, 7 patients), and undifferentiated CTD (UCTD, 9 patients). Antinuclear matrix antibodies were detected using indirect immunofluorescence staining on HCl-treated HEp-2 cells. The antinuclear matrix antibody titer was significantly higher in serum from patients with MCTD or SSc than in serum from patients with SLE or UCTD. The antinuclear matrix antibody titer was significantly increased in serum from patients with sclerodactyly, pitting scars, contracture of the phalanges, and decreased carbon monoxide diffusion capacity. Thus, a higher titer of antinuclear matrix antibodies in serum from patients with anti-U1RNP antibodies may be associated with a clinical diagnosis of MCTD or SSc rather than a diagnosis of SLE or UCTD. Received: 6 July 1999 / Revised: 11 October 1999 / Accepted: 27 October 1999     

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.     

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 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.