Serum TIMP-1, TIMP-2, and MMP-1 in patients with systemic sclerosis, primary Raynaud's phenomenon, and in normal controls

BACKGROUND: Excess tissue matrix accumulates in systemic sclerosis (SSc), accounting for both visceral and dermal fibrosis. It is suggested that decreased serum levels of matrix metalloproteinases (MMPs) or increased levels of tissue inhibitors of matrix metalloproteinases (TIMPs) may account for this matrix accumulation. OBJECTIVE: To measure serum levels of tissue inhibitors of metalloproteinases, TIMP-1, TIMP-2, and collagenase-1 (MMP-1), in patients with diffuse cutaneous systemic sclerosis (dcSSc), limited cutaneous systemic sclerosis (lcSSc), primary Raynaud's phenomenon (RP), and in normal controls. METHODS: Serum samples from patients with dcSSc (n=83), lcSSc (n=87), RP (n=80), and normal controls (n=98) were analysed using enzyme linked immunosorbent assays (ELISAs) for total TIMP-1, TIMP-2, and MMP-1. Results from each assay were analysed by the Kruskal-Wallis test. Dunn's multiple comparison post-test was then applied between groups. RESULTS: TIMP-1 levels were significantly raised in dcSSc and lcSSc groups compared with the RP group and normal controls (p<0.01 to p<0.001). In the dcSSc group, TIMP-1 levels were significantly higher in early disease (<2 years) than in late stage disease (>4 years) (p<0.05). This was not found for the lcSSc group. Serum TIMP-2 and MMP-1 levels in dcSSc and lcSSc did not differ significantly from those in normal controls. Increased levels of TIMPs were not convincingly associated with organ disease. No assay result correlated with autoantibody status (anti-topoisomerase 1 (anti-Scl-70), anticentromere antibody, or anti-RNA polymerase). No significant differences in serum TIMP-1, TIMP-2, or MMP-1 levels were shown in the RP group compared with normal controls. CONCLUSIONS: Raised TIMP-1 levels in the SSc groups support the hypothesis that matrix accumulation occurs in SSc at least in part owing to decreased degradation. Moreover, the variation in TIMP-1 levels between the early and late disease stages of dcSSc seems to reflect the early progressive course of dermal fibrosis seen clinically. The expected reduction in serum MMP-1 levels in the SSc groups was not found. This suggests that tissue matrix accumulation is due to increased inhibitors rather than to decreased MMPs.     

Serum levels of soluble CD21 in patients with systemic sclerosis

Systemic sclerosis (SSc) is a systemic disorder that typically results in fibrosis of the skin and multiple internal organ systems. Although the precise mechanism is unknown, overproduction of extracellular matrix proteins, including collagens and fibronectins, and aberrant immune activation might be involved in the pathogenesis. The soluble cluster of differentiation 21 (sCD21) represents the extracellular portion of the CD21 glycoprotein that is released by shedding from the cell surfaces into plasma. sCD21 binds complement fragments and activates monocytes through binding to membrane CD23. The present study was undertaken to investigate the serum levels of sCD21 in patients with SSc. Serum sCD21 levels were reduced with age both in patients with SSc and normal controls. Serum sCD21 levels in patients with SSc were significantly decreased compared to those in control subjects. When we divided patients with SSc into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc), patients with lcSSc had lower levels of serum sCD21 than those with dcSSc. Moreover, the prevalence of pulmonary fibrosis in the patients with dcSSc inversely correlated with serum sCD21 levels. Our finding may support the notion that B-cell activation is involved in the mechanism for pulmonary fibrosis and skin sclerosis.     

Clinical significance of serum matrix metalloproteinase-13 levels in patients with localized scleroderma

OBJECTIVES: To investigate the clinical significance of serum matrix metalloproteinase-13 (MMP-13) levels in patients with localized scleroderma (LSc). METHODS: Serum MMP-13 levels were determined by using a peptide substrate cleavage assay in 10 patients with generalized morphea, 10 with linear scleroderma, 10 with morphea, and 10 normal controls. RESULTS: The serum MMP-13 levels in patients with LSc were lower than those in normal controls, but there was no significant difference (64.9 +/- 19.9 versus 73.2 +/- 11.5, p = 0.058). Serum MMP-13 levels in patients with generalized morphea were significantly lower than those in normal controls (54.0 +/- 18.7 versus 73.2 +/- 11.5 ng/ml; p < 0.01). Serum levels of MMP-13 were comparable among normal controls, the patients with linear scleroderma, and those with morphea. The prevalence of muscle involvement was significantly greater in the LSc patients with decreased MMP-13 levels compared with those with normal MMP-13 levels (50% versus 8%, p < 0.05). Serum MMP-13 levels were significantly inversely correlated with the number of linear lesions (r = 0.366, p < 0.05) and the number of involved body areas (r = 0.552, p < 0.005) in patients with LSc, while there was no significant correlation between serum MMP-13 levels and the number of plaque lesions. Furthermore, there was significant inverse correlation between serum MMP-13 levels and the number of involved body areas in patients with generalized morphea (r = 0.631, p < 0.05). CONCLUSION: The serum MMP-13 levels may reflect the disease severity in patients with LSc, especially generalized morphea, the severest form of this disorder.     

A novel autoantigen to differentiate limited cutaneous systemic sclerosis from diffuse cutaneous systemic sclerosis: the interferon-inducible gene IFI16

OBJECTIVE: To investigate the presence and clinical significance of autoantibodies against the interferon-inducible gene IFI16 in systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and other autoimmune diseases. METHODS: Immunohistochemical analysis was used to evaluate the expression of IFI16 in skin biopsy specimens obtained from patients with SSc and patients with SLE. Levels of antibodies against IFI16 in sera from 82 patients with SSc and 100 patients with SLE were determined by enzyme-linked immunosorbent assay. Other autoimmune diseases such as primary Sj?gren's syndrome (SS), rheumatoid arthritis (RA), chronic urticaria, and hepatitis C virus (HCV) infection were also examined. RESULTS: Expression of IFI16 was greatly increased and was ubiquitous in all layers of the epidermis and in the dermal inflammatory infiltrates of lesional skin from both patients with SLE and patients with SSc. Patients with SLE, those with primary SS, and those with SSc exhibited significantly higher anti-IFI16 IgG antibody levels compared with normal controls (for SLE, P < 0.002; for primary SS, P < 0.001; for SSc, P < 0.0005). Anti-IFI16 titers above the ninety-fifth percentile for control subjects were observed in 26% of the patients with SLE, 50% of those with primary SS, and 21% of those with SSc (28% of patients with limited cutaneous SSc [lcSSc] versus 4% of patients with diffuse cutaneous SSc [dcSSc]). In contrast, the prevalence of anti-IFI16 was 4% in patients with RA, 5% in those with chronic urticaria, and 13% in those with HCV infection. CONCLUSION: The results of this study provide evidence that an IFN-inducible gene, IFI16, may be involved in the pathophysiologic mechanisms of connective tissue disorders such as SSc. Moreover, a strict correlation with lcSSc was also demonstrated, thus providing a novel tool in the differential diagnosis of lcSSc from dcSSc.     

Increased serum soluble CD40 levels in patients with systemic sclerosis

OBJECTIVE: To determine serum levels of soluble CD40 (sCD40) and clinical association in patients with systemic sclerosis (SSc). METHODS: Serum sCD40 levels were examined by ELISA in 49 patients with SSc, 15 patients with systemic lupus erythematosus, and 26 healthy individuals. sCD40 levels in plasma samples, which were obtained at the same time, were also determined. SSc patients were grouped into 22 patients with limited cutaneous SSc (lcSSc) and 27 patients with diffuse cutaneous SSc (dcSSc). RESULTS: There was no significant difference between sCD40 levels of sera and those of plasma. Serum sCD40 levels were significantly elevated in patients with SSc compared to patients with systemic lupus erythematosus and controls (p < 0.001). Serum sCD40 levels were higher in patients with lcSSc than in those with dcSSc (p <0.001). There was no correlation between sCD40 and sCD40 ligand levels in patients with SSc. CONCLUSION: Elevated serum sCD40 levels were associated with lcSSc. These results suggest that the blockade of CD40/CD40 ligand interaction could be a potential therapeutic strategy in SSc.     

Disease subsets, antinuclear antibody profile, and clinical features in 127 French and 247 US adult patients with systemic sclerosis

OBJECTIVE: To investigate the specificities of antinuclear antibodies (ANA) associated with systemic sclerosis (SSc) disease classification and internal organ involvement among patients with SSc of different origins (European and American). METHODS: Serum samples from 374 adult patients diagnosed with SSc were studied: 127 French patients (Paris) were compared with 247 US patients (Pittsburgh). Patients were classified into diffuse cutaneous (dc) and limited cutaneous (lc) SSc subsets. Antibodies associated with SSc were determined by protein and/or RNA immunoprecipitation, indirect immunofluorescence, and immunodiffusion. RESULTS: SSc classification differed significantly in the 2 cohorts: lcSSc and overlap patients with lcSSc combined made up 76% of the French series versus 52% of the US group (p < 0.0001). The frequency of anti-RNA polymerase III antibody was significantly increased in US patients compared with French patients (p < 0.0001). The frequency of anti-topoisomerase I (topo I) antibody was significantly increased among French patients (p < 0.0048). Anti-topo I-positive French SSc patients were less likely to have dcSSc (38% vs 65%) and more likely to have milder disease than US anti-topo I-positive patients. The French dcSSc patients had lower proportions of joint/tendon manifestations and renal crisis (7% vs 17%), but more often had radiographic evidence of pulmonary fibrosis (57% vs 30%). French lcSSc patients had a lower frequency of pulmonary arterial hypertension than US lcSSc patients (9% vs 31%; p = 0.002). CONCLUSION: There are disease classification and SSc-related serum autoantibody differences between French and American patients with SSc. These differences help to explain variations in clinical features reported from different geographic regions.     

Circulating levels of active transforming growth factor beta1 are reduced in diffuse cutaneous systemic sclerosis and correlate inversely with the modified Rodnan skin score

OBJECTIVES: To determine the relationship between clinical features and circulating levels of active transforming growth factor (TGF) beta1 in the major subsets of systemic sclerosis (SSc). METHODS: In a cross-sectional study cases of diffuse cutaneous SSc (dose) (n = 27) or limited cutaneous SSc (dose) (n = 20) were compared with healthy controls (n = 22). Active and total TGFbeta1 was measured in serum and plasma by a high-sensitivity enzyme-linked immunosorbent assay. RESULTS: There were no significant differences between levels of total serum TGFbeta1. However, cases of dcSSc had lower levels of active TGFbeta1 than cases of lcSSc or controls. In addition, more cases of dcSSc (18/27; 66%, P < 0.025) had no detectable active TGFbeta1 than controls (7/22, 32%) or lcSSc (7/20, 35%). In dcSSc, serum active TGFbeta1 levels correlated negatively with skin score and positively with disease duration. CONCLUSIONS: Contrary to expectation, levels of active TGFbeta1 are reduced in dcSSc and this correlates with two variables known to associate with disease activity, shorter duration and more extensive skin sclerosis. This suggests that active TGFbeta1 may be sequestered in active involved SSc skin and that serum levels are reduced despite strong evidence implicating TGFbeta isoforms in the pathogenesis of fibrosis. Our findings may have implications for systemic TGFbeta-trapping therapies in this disease.     

High-resolution CT scan findings in patients with symptomatic scleroderma-related interstitial lung disease

BACKGROUND: Lung disease has become the leading cause of mortality and morbidity in scleroderma (SSc) patients. The frequency, nature, and progression of interstitial lung disease seen on high-resolution CT (HRCT) scans in patients with diffuse SSc (dcSSc) compared with those with limited SSc (lcSSc) has not been well characterized. METHODS: Baseline HRCT scan images of 162 participants randomized into a National Institutes of Health-funded clinical trial were compared to clinical features, pulmonary function test measures, and BAL fluid cellularity. The extent and distribution of interstitial lung disease HRCT findings, including pure ground-glass opacity (pGGO), pulmonary fibrosis (PF), and honeycomb cysts (HCs), were recorded in the upper, middle, and lower lung zones on baseline and follow-up CT scan studies. RESULTS: HRCT scan findings included 92.9% PF, 49.4% pGGO, and 37.2% HCs. There was a significantly higher incidence of HCs in the three zones in lcSSc patients compared to dcSSc patients (p = 0.034, p = 0.048, and p = 0.0007, respectively). The extent of PF seen on HRCT scans was significantly negatively correlated with FVC (r = - 0.22), diffusing capacity of the lung for carbon monoxide (r = - 0.44), and total lung capacity (r = - 0.36). A positive correlation was found between pGGO and the increased number of acute inflammatory cells found in BAL fluid (r = 0.28). In the placebo group, disease progression was assessed as 30% in the upper and middle lung zones, and 45% in the lower lung zones. No difference in the progression rate was seen between lcSSc and dcSSc patients. CONCLUSIONS: PF and GGO were the most common HRCT scan findings in symptomatic SSc patients. HCs were seen in more than one third of cases, being more common in lcSSc vs dcSSc. There was no relationship between progression and baseline PF extent or lcSSc vs dcSSc. Trial registration: Clinicaltrials.gov Identifier: NCT00004563.     

Circulating collagen metabolites in systemic sclerosis. Differences between limited and diffuse form and relationship with pulmonary involvement

OBJECTIVE: To study collagen metabolites in systemic sclerosis (SSc) and their relationship with clinical manifestations of the disease. METHODS: Forty-eight SSc patients, 13 with a diffuse form (dcSSc), 23 with a limited form (lcSSc) and 12 with suspected SSc not fulfilling the ACR criteria, and 31 healthy controls were examined. Serum concentrations of aminoterminal type III procollagen peptide (PIIINP), aminoterminal and carboxyterminal type I procollagen peptides (PINP and PICP) and cross-linked carboxyterminal telopeptide of collagen I (ICTP) were determined by radioimmunoassay. RESULTS: Increased serum concentrations of ICTP were found in SSc patients compared with controls. Distinctly higher levels of ICTP were observed in dcSSc than in lcSSc. High serum ICTP was correlated with skin score and acute phase reactants, and with reduced pulmonary function. Serum PIIINP concentration was elevated in both lcSSc and dcSSc. CONCLUSION: Augmented collagen catabolism accompanies the increased collagen synthesis in SSc. Serum ICTP concentration is a marker of this feature and also reflects clinical severity.     

Effector CD8+ T cells in systemic sclerosis patients produce abnormally high levels of interleukin‐13 associated with increased skin fibrosis

Objective

T lymphocytes play an important role in systemic sclerosis (SSc), a connective tissue disease characterized by inflammation, fibrosis, and vascular damage. While their precise role and antigen specificity are unclear, T cell–derived cytokines likely contribute to the induction of fibrosis. The aim of this study was to establish the role of cytokine dysregulation by T cells in the pathogenesis of SSc.

Methods

To identify relationships between a specific cytokine, T cell subset, and the disease course, we studied a large cohort of patients with diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc). Using Luminex analysis and intracellular cytokine staining, we analyzed the intrinsic ability of CD4+ and CD8+ T cell subsets to produce cytokines following in vitro activation.

Results

High levels of the profibrotic type 2 cytokine interleukin‐13 (IL‐13) were produced following activation of peripheral blood effector CD8+ T cells from SSc patients as compared with normal controls or with patients with rheumatoid arthritis. In contrast, CD4+ T cells showed a lower and more variable level of IL‐13 production. This abnormality correlated with the extent of fibrosis and was more pronounced in dcSSc patients than in lcSSc patients.

Conclusion

Dysregulated IL‐13 production by effector CD8+ T cells is important in the pathogenesis of SSc and is critical in the predisposition to more severe forms of cutaneous disease. Our study is the first to identify a specific T cell phenotype that correlates with disease severity in SSc and can be used as a marker of immune dysfunction in SSc and as a novel therapeutic target.

     

Pulmonary capillary endothelial dysfunction in early systemic sclerosis

OBJECTIVE: Pulmonary capillary endothelium-bound angiotensin-converting enzyme (PCEB-ACE) activity is a sensitive and quantifiable index of endothelial function in vivo. Systemic sclerosis (SSc) is characterized by endothelial damage and excess collagen formation, causing mainly pulmonary hypertension (PH) in the limited cutaneous SSc (lcSSc) subset and interstitial lung disease with pulmonary interstitial fibrosis (PIF) in the diffuse cutaneous SSc (dcSSc) subset. This study was undertaken to investigate the hypothesis that PCEB-ACE activity is reduced early in SSc, in the absence of PH or PIF. METHODS: Applying indicator-dilution techniques, we measured single-pass transpulmonary hydrolysis and percent metabolism (%M) of a synthetic ACE substrate and calculated functional capillary surface area (FCSA) in 25 SSc patients and 11 controls. Substrate hydrolysis and %M reflect ACE activity per capillary; FCSA reflects ACE activity per vascular bed. RESULTS: PCEB-ACE activity was decreased in both SSc subsets. Among patients without PH, substrate hydrolysis and %M were decreased in patients with lcSSc and more profoundly in those with dcSSc; loss of FCSA normalized to body surface area (FCSA/BSA) was observed in dcSSc, but not in lcSSc. High-resolution computed tomography of the lung, performed in all SSc patients, revealed no correlation between substrate %M, hydrolysis, or FCSA/BSA and the degree of PIF; 5 dcSSc and 5 lcSSc patients with no detectable PIF exhibited decreases in hydrolysis and %M, while FCSA/BSA was decreased only in dcSSc. CONCLUSION: Depression of PCEB-ACE activity, indicating pulmonary endothelial dysfunction, occurs early in SSc, in the absence of PH or PIF, and is more pronounced, at this early pulmonary disease stage, in dcSSc than in lcSSc.     

Association of markers for TGFbeta3, TGFbeta2 and TIMP1 with systemic sclerosis

OBJECTIVES: To investigate whether six microsatellite markers known to map closely to genes involved in fibrosis are associated with systemic sclerosis (SSc). METHODS: Markers mapping to TGFbeta1, TGFbeta2, TGFbeta3, PDGFB, TIMP1 and COL5A2 were genotyped and allele frequency distributions compared in 191 patients and 196 controls. As TIMP1 maps to the X chromosome, male and females were analysed separately. Markers associated with SSc were further investigated according to whether patients had limited (lcSSc) or diffuse (dcSSc) cutaneous fibrosis. RESULTS: Associations were found between SSc and markers for TGFbeta3 (chi(2)=17.3, df=8, P=0.02), TGFbeta2 (chi(2)=25.2, df=13, P=0.02) and TIMP1 (with male SSc, chi(2)=11.9, df=5, P=0.03), between lcSSc and the TGFss2 marker (chi(2)=25.6, df=13, P=0.02), and between dcSSc and TGFbeta3 marker (chi(2)=27.1, df=8, P=0.001). Between lcSSc and dcSSc patients, the allele frequency distribution differed only for the TGFbeta3 marker (chi(2)=16.5, df=6, P=0.01). CONCLUSION: These associations indicate a possible role for TGFbeta3, TGFbeta2 and TIMP1 in genetic susceptibility to SSc and for TGFbeta3 in determining the degree of cutaneous fibrosis.     

特发性肺纤维化患者支气管肺泡灌洗液和血清基质金属蛋白酶及其抑制剂检测

目的探讨特发性肺纤维化(IPF)患者支气管肺泡灌洗液(BALF)及血清中基质金属蛋白酶9(MMP9)、基质金属蛋白酶组织抑制剂1(TIMP1)水平的变化。方法2001至2004年用酶联免疫吸附(ELISA)法检测30例IPF患者BALF及血清中MMP9和TIMP1的水平,同时行肺高分辨率CT(HRCT)及肺功能检查。健康非吸烟的自愿献血者30名,为血清对照组。以胸痛为自觉症状在我院自愿进行纤维支气管镜及BALF检查,经体检及X线检查证实为健康者13名,作为BALF对照组。结果IPF患者BALF及血清中MMP9水平为(245±26)和(203±32)ng/L,对照组为(205±22)和(186±16)ng/L,两组相比差异无统计学意义;IPF组BALF及血清中TIMP1水平[(522±81)、(166±29)ng/L]高于对照组[(201±31)、(87±16)ng/L],差异有统计学意义;IPF组BALF及血清中MMP9/TIMP1比值(0.53±0.18,1.5±0.3)低于对照组(1.06±0.38,2.6±0.5)。HRCT、肺功能评分及BALF中上述指标与MMP9无明显相关性,与TIMP1呈正相关,与MMP9/TIMP1比值呈负相关。结论IPF患者肺纤维化的发生与TIMP1水平升高及MMP9/TIMP1比值降低对细胞外基质降解的抑制有关,后者可能意义更大;患者肺影像学及肺功能变化可能也与此有关。     

Serum levels of KL-6 as a useful marker for evaluating pulmonary fibrosis in patients with systemic sclerosis

OBJECTIVE: KL-6 is a mucin-like glycoprotein that is strongly expressed on type II pneumocytes in the lung. Circulating KL-6 has been shown to be a sensitive marker of the disease activity of interstitial lung diseases. We determined the serum levels of KL-6 in patients with systemic sclerosis (SSc) and investigated whether these levels would serve as a useful marker of pulmonary fibrosis (PF) in patients with SSc. METHODS: The serum KL-6 levels were determined using a specific ELISA in 91 patients with SSc, and in 38 healthy controls. RESULTS: The serum levels of KL-6 were significantly higher in patients with SSc than in healthy controls (923+/-860 vs. 382+/-55 U/ml; p<0.0001). The serum KL-6 levels of the patients with diffuse cutaneous SSc (dSSc) tended to be higher than those with limited cutaneous SSc (ISSc) (1054+/-1000 vs. 800+/-694 U/ml), but there was no significant difference between these 2 groups. The serum KL-6 levels in the patients with PF were significantly elevated compared to those without PF (1283+/-1056 vs. 520+/-148 U/ml; p<0.0001). Moreover, DLCO and VC were also significantly decreased in the patients with elevated KL-6 levels compared to those with normal levels (62+/-22% vs. 72+/-17%, p<0.05; 87 +/-20% vs. 100+/-18%, p<0.01, respectively). CONCLUSION: Serum KL-6 level may be a useful serum marker for evaluating pulmonary fibrosis in patients with SSc.     

Decreased ratio of circulatory vascular endothelial growth factor to endostatin in patients with systemic sclerosis--association with pulmonary involvement

OBJECTIVE: Vascular endothelial growth factor (VEGF) and endostatin appear to be involved in development of systemic sclerosis (SSc). We undertook this study to determine ratios of serum concentrations of VEGF to endostatin in SSc patients, healthy controls, assessments between cytokines, and lung-diffusing capacity (DLCO) as lung injury measurements related to interstitial lung disease (ILD). MATERIALS AND METHODS: Serum VEGF and endostatin levels were measured with ELISA in 28 SSc patients (16 with lcSSc) and 20-matched healthy volunteers, evaluating correlation and balance. DLCO was corrected for hemoglobin, alveolar volume, and determined with a single breath technique. RESULTS: SSc serum concentrations (median; range) of endostatin were higher than controls (107.2; 13.6-261.2 vs. 77.8; 18.0-110.4 ng/ml, p < 0.05); VEGF levels did not differ (151.2; 4.5-836.4 vs. 286.4; 23.7-708.5 pg/ml, p < 0.05). Ratios of VEGF to endostatin were 2.6 and 3.6 times lower (p < 0.05) in SSc and dcSSc in comparison to healthy subjects. There were significant negative correlations between VEGF, endostatin in SSc (r = -0.51), and controls (r = -0.57). SSc with ILD (n = 20) had similar concentrations of VEGF, endostatin, and ratios of VEGF to endostatin compared to SSc alone. No correlations were seen between DLCO, VEGF, endostatin and their ratios in the whole SSc group. Negative correlations were noted between DLCO and VEGF (r = -0.82), with DLCO and the ratio of VEGF to endostatin (-0.62) in lcSSc with ILD (n = 10). CONCLUSION: Decreased ratios of VEGF to endostatin may reflect imbalances between serum angiogenic, and anti-angiogenic activity in SSc, explaining impaired neoangiogenesis.     

Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti-topoisomerase I antibody

OBJECTIVE: To describe the clinical and laboratory features and natural history of the disease in systemic sclerosis (SSc; scleroderma) patients with anti-topoisomerase I (anti-topo I) antibody who have different skin thickness progression rates (STPRs). METHODS: SSc patients (n = 212) who were anti-topo I antibody positive were divided into 5 subgroups based on STPRs. Skin thickness was measured using the modified Rodnan skin thickness score (MRSS). Anti-topo I IgG antibody levels were determined. RESULTS: Sixty patients who were anti-topo I antibody positive had diffuse cutaneous SSc (dcSSc) with rapid progression, 82 had dcSSC with intermediate progression, and 29 had dcSSc with slow progression, 14 had limited cutaneous SSc (lcSSc) that became dcSSc, and 27 had lcSSc that did not change throughout. Patients beginning with lcSSc were younger at disease onset and had longer disease duration when diagnosed as having SSc. Interstitial lung disease was common and was equally distributed across the subgroups. Renal crisis occurred most often in patients with rapid progression (22%) and was absent in lcSSc patients. Cardiac involvement was most frequent in the dcSSc subgroups. Both kidney and heart disease occurred most often within 3 years after the onset of skin thickening. The 10-year cumulative survival rate was <40% for patients with rapid and intermediate progression. Renal and cardiac causes of death were disproportionately frequent in these 2 subgroups. Anti-topo I antibody levels correlated with the STPR and the MRSS. CONCLUSION: Anti-topo I antibody-positive patients with SSc with a rapid STPR have reduced survival rates, primarily due to early and often fatal renal and cardiac involvement. Anti-topo I antibody levels parallel the MRSS at the first visit and the STPR. This information is important for managing physicians and researchers planning clinical trials involving patients with early dcSSc.     

Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of scleroderma

OBJECTIVE: To investigate the potential association between functional polymorphisms in the gene for the innate mediator, macrophage migration inhibitory factor (MIF), and the clinical expression of systemic sclerosis (SSc). METHODS: Genomic DNA samples and clinical data were collected from the Scleroderma Family Registry and DNA Repository at the University of Texas Health Science Center at Houston. A total of 740 subjects were studied; 203 of them had diffuse cutaneous SSc (dcSSc), 283 had limited cutaneous SSc (lcSSc), and the remaining 254 healthy subjects served as controls. Association analyses were performed on the whole data set and on patient and sex subsets. Significant relationships were determined between clinical variables and MIF polymorphisms for each disease subtype in the studied groups. RESULTS: The frequency of the -173*C MIF allele, which was previously reported to be associated with high production of MIF, was lower in the lcSSc group (12.6%) than in the dcSSc (19.2%) or control (18.5%) groups (P = 0.010 and P = 0.011, respectively). Haplotype analysis for 2 closely linked polymorphisms in the MIF promoter showed that in white subjects with lcSSc or dcSSc, the lcSSc population had a significantly lower representation of the high-expression MIF haplotype defined by -173*C and -794 with 7 CATT repeats (C7) (P = 0.015, odds ratio 1.94 [95% confidence interval 1.14-3.32]). Fibroblasts encoding the C7 MIF haplotype were observed to produce more MIF upon in vitro stimulation than those with a non-C7 haplotype. CONCLUSION: Functional promoter polymorphisms in the MIF gene affect the clinical presentation of SSc. The proinflammatory haplotype defined by C7 is underrepresented in patients with lcSSc.     

Clinical and serological features of systemic sclerosis in a Chinese cohort

Our goal was to study the prevalence of systemic sclerosis (SSc) subtypes, autoantibody profile, and pulmonary fibrosis in a large group of Han Chinese. Chinese SSc patients (n?=?419) were recruited from a multicenter study including hospitals and outpatient clinics in China. All patients met the American College of Rheumatology classification criteria for SSc. Anti-topoisomerase (ATA), anti-centromere (ACA), anti-RNA polymerase III (anti-RNAP3), and anti-U1-ribonucleoprotein (anti-U1RNP) were detected utilizing commercially available kits. The clinical and autoantibody information in Chinese patients was compared to that in the US Caucasian patients (n?=?834), recruited from the Genetics versus Environment in Scleroderma Outcome Study and Scleroderma Family Registry. Chi-square test was utilized for the abovementioned comparisons. Chinese patients showed 40.3 % limited (lcSSc) and 59.7 % diffuse (dcSSc) forms of SSc. ATA was found in 59.9 %, ACA in 13.4 %, anti-RNAP3 in 1.3 %, and anti-U1RNP in 18 % of Chinese SSc patients. Compared to US patients (65.1 % lcSSc, 34.9 % dcSSc, ATA in 18.7 %, ACA in 32.4 %, anti-RNAP3 in 17.4 %, and anti-U1RNP in 2.8 %), Chinese SSc patients are significantly higher in dcSSc and the frequencies of ATA and anti-U1RNP, but lower in ACA and anti-RNAP3. In addition, pulmonary fibrosis was observed in 78 % Chinese SSc patients and was strongly associated with the presence of ATA. The present study represents the first report of SSc features in a large group of Chinese patients. Clinical subtypes and the frequencies of SSc-related autoantibodies in Chinese SSc patients are significantly different from those in SSc patients of the US Caucasian descent.     

Clinical subsets,skin thickness progression rate,and serum antibody levels in systemic sclerosis patients with anti–topoisomerase I antibody

Objective

To describe the clinical and laboratory features and natural history of the disease in systemic sclerosis (SSc; scleroderma) patients with anti–topoisomerase I (anti–topo I) antibody who have different skin thickness progression rates (STPRs).

Methods

SSc patients (n = 212) who were anti–topo I antibody positive were divided into 5 subgroups based on STPRs. Skin thickness was measured using the modified Rodnan skin thickness score (MRSS). Anti–topo I IgG antibody levels were determined.

Results

Sixty patients who were anti–topo I antibody positive had diffuse cutaneous SSc (dcSSc) with rapid progression, 82 had dcSSC with intermediate progression, and 29 had dcSSc with slow progression, 14 had limited cutaneous SSc (lcSSc) that became dcSSc, and 27 had lcSSc that did not change throughout. Patients beginning with lcSSc were younger at disease onset and had longer disease duration when diagnosed as having SSc. Interstitial lung disease was common and was equally distributed across the subgroups. Renal crisis occurred most often in patients with rapid progression (22%) and was absent in lcSSc patients. Cardiac involvement was most frequent in the dcSSc subgroups. Both kidney and heart disease occurred most often within 3 years after the onset of skin thickening. The 10‐year cumulative survival rate was <40% for patients with rapid and intermediate progression. Renal and cardiac causes of death were disproportionately frequent in these 2 subgroups. Anti–topo I antibody levels correlated with the STPR and the MRSS.

Conclusion

Anti–topo I antibody–positive patients with SSc with a rapid STPR have reduced survival rates, primarily due to early and often fatal renal and cardiac involvement. Anti–topo I antibody levels parallel the MRSS at the first visit and the STPR. This information is important for managing physicians and researchers planning clinical trials involving patients with early dcSSc.

     

Clinical correlation of brachial artery flow-mediated dilation in patients with systemic sclerosis

Abstract

Objective To investigate the clinical significance of flow-mediated dilation (FMD) in systemic sclerosis (SSc).

Methods Thirty-three SSc patients and 12 healthy controls were studied. Ultrasound assessment of the brachial artery FMD was performed on all subjects. The results were expressed as the percentage of increase in brachial artery diameter following hyperemia.

Results Limited cutaneous SSc (lcSSc) patients had significantly lower FMD values than healthy controls (5.3 ± 2.7 versus 7.7 ± 2.0 %, p < 0.05), while the values in diffuse cutaneous SSc (dcSSc) patients (6.7 ± 4.0 %) were comparable to those in lcSSc patients and healthy controls. Although FMD values did not correlate with any clinical features in dcSSc patients, there was an inverse correlation between FMD values and disease duration in lcSSc patients (r = ?0.64, p < 0.05). Furthermore, lcSSc patients with decreased FMD values showed significantly higher prevalence of digital ulcers and elevated right ventricular systolic pressure than those with normal values (for each; 75 versus 10 %, p < 0.05).

Conclusion The FMD values represent the severity of vascular damages, which progress along with disease duration and lead to digital ulcers and pulmonary arterial hypertension, in lcSSc patients.