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.     

Registry of the Spanish Network for Systemic Sclerosis: Survival,Prognostic Factors,and Causes of Death

Systemic sclerosis (SSc) is a rare, multisystem disease showing a large individual variability in disease progression and prognosis. In the present study, we assess survival, causes of death, and risk factors of mortality in a large series of Spanish SSc patients. Consecutive SSc patients fulfilling criteria of the classification by LeRoy were recruited in the survey. Kaplan–Meier and Cox proportional-hazards models were used to analyze survival and to identify predictors of mortality. Among 879 consecutive patients, 138 (15.7%) deaths were registered. Seventy-six out of 138 (55%) deceased patients were due to causes attributed to SSc, and pulmonary hypertension (PH) was the leading cause in 23 (16.6%) patients. Survival rates were 96%, 93%, 83%, and 73% at 5, 10, 20, and 30 years after the first symptom, respectively. Survival rates for diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc were 91%, 86%, 64%, and 39%; and 97%, 95%, 85%, and 81% at 5, 10, 20, and 30 years, respectively (log-rank: 67.63, P < 0.0001). The dcSSc subset, male sex, age at disease onset older than 65 years, digital ulcers, interstitial lung disease (ILD), PH, heart involvement, scleroderma renal crisis (SRC), presence of antitopoisomerase I and absence of anticentromere antibodies, and active capillaroscopic pattern showed reduced survival rate. In a multivariate analysis, older age at disease onset, dcSSc, ILD, PH, and SRC were independent risk factors for mortality. In the present study involving a large cohort of SSc patients, a high prevalence of disease-related causes of death was demonstrated. Older age at disease onset, dcSSc, ILD, PH, and SRC were identified as independent prognostic factors.     

Incidence and predictors of interstitial lung disease (ILD) in Thai patients with early systemic sclerosis: Inception cohort study

Objectives: To determine and compare the prevalence of interstitial lung disease (ILD), the severity of high-resolution computed tomography (HRCT) score and incidence rate (IR) of ILD between the two subsets of early-SSc (systemic sclerosis) patients. We also determined the factors associated with ILD.

Methods: We used an inception cohort of early-SSc patients seen between January 2010 and June 2014. All patients underwent HRCT at study entry and annually thereafter.

Results: One hundred and thirteen patients (66 females and 89 diffuse cutaneous SSc [dcSSc]) with a mean?±?SD age of 53.4?±?8.4 years and mean disease duration of 12.9?±?10.3 months at cohort entry were enrolled. At enrollment, patients with dcSSc had a higher prevalence of ILD (78.7% vs. 45.8%, p?=?0.002), and a higher total HRCT score (10.3?±?9.5 vs. 4.4?±?5.6, p?=?0.001) compared with limited cutaneous SSc (lcSSc). DcSSc patients had a higher IR of ILD than lcSSc patients (58.8 vs.17.3 per 100 person-years, p?<?0.001). Univariable analysis revealed that male gender, presence of anti-Scl 70 and absent anti-centromere antibody was significant predictors of ILD. In Cox-regression analysis, a positive anti-centromere [hazard ratio (HR) 0.09 95% confidence interval (95% CI 0.01–0.73)] was a protective factor.

Conclusions: DcSSc patients had more severe HRCT scores and higher IR of ILD compared with lcSSc patients. Male gender, presence of anti-Scl 70, and absent anti-centromere antibody predicted the future development of ILD in early-SSc patients.     

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.     

Anti-fibrillarin antibodies in systemic sclerosis

OBJECTIVES: To investigate the nature and extent of organ involvement in anti-fibrillarin antibody (AFA)-positive patients within a UK systemic sclerosis (SSc) population. METHODS: We investigated 1026 consecutive patients with SSc. AFA was identified by the characteristic clumpy nucleolar and coilin body pattern of staining in interphase cells and staining of fibrillarin in metaphase cells by indirect immunofluorescence using HEp-2 cells. Identity of the 34-kDa fibrillarin protein was confirmed by immunoprecipitation from [(35)S]methionine-labelled HeLa cell extract. RESULTS: AFA was detected in 42 patients (4.1%) with early disease onset (mean age 36 yr). Sixteen (38%) patients had limited cutaneous (lcSSc) and 26 (62%) diffuse cutaneous SSc (dcSSc). All eight Afro-Caribbean patients with AFA had dcSSc whereas the Caucasians were equally divided between dcSSc and lcSSc. Within the dcSSc subgroup, 54% had myositis, 35% had pulmonary hypertension, 15% had cardiac involvement and 23% had renal involvement. CONCLUSIONS: AFA identifies young SSc patients with frequent internal organ involvement, especially pulmonary hypertension, myositis and renal disease. In contrast to previous reports, AFA was not restricted to dcSSc patients in Caucasians.     

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.     

Different clinical features in patients with limited and diffuse cutaneous systemic sclerosis

This study aims to analyze differences among established disease damage indicators in patients with limited cutaneous systemic sclerosis (lcSSc) and diffuse cutaneous systemic sclerosis (dcSSc). Fifty patients with lcSSc and 55 patients with dcSSc were included in this study. Difference in mean disease duration between the two subgroups of patients was not statistically significant (z=−0.88, p=0.38). Patients with lcSSc and dcSSc were compared, and differences in vascular, esophageal, lung, heart, renal, and musculoskeletal involvement were statistically assessed using χ ², Mann–Whitney, and Kruskal–Wallis tests. Using the technique of nailfold capillaroscopy, we found normal capillaries or nonspecific capillary change in 10.0% of the patients with lcSSc and only in 3.6% of the patients with dcSSc. Dilated capillaries without loss of capillaries were found in 42% of the patients with lcSSc and in 10.9% of the patients with dcSSc (p=0.05). However, severe capillary damage (loss of capillaries) was noticed more frequently in patients with dcSSc (dcSSc/lcSSc: 85.5%/48.0%, p=0.002). Pitting scars or digital ulcers were found in 46.0% of the patients with lcSSc and in 67.3% of the patients with dcSSc (p=0.04). We did not notice a significant difference in frequency of fingertip osteolysis and telangiectasia. Esophageal hypomotility was found in 64% of the patients with lcSSc and in 85.5% of the patients with dcSSc (p<0.01). We found interstitial lung fibrosis more frequently in patients with dcSSc (lcSSc/dcSSc: 16.0%/72.7%, p<0.001). Reduced forced vital capacity (FVC) was found in 6.0% of the of patients with lcSSc and in 41.8% of the patients with dcSSc (p<0.001). A decreased value of the transfer factor for carbon monoxide (DLCO) was also observed more frequently in patients with dcSSc. Heart involvement was found in 29.1% of the patients with dcSSc and less frequently (p<0.001) in patients with lcSSc (8%). Similarly, we found renal involvement more frequently in patients with dcSSc (lcSSc/dcSSc: 2.0%/16.3%). Tendon friction rubs were noticed in 23.6% of the patients with dcSSc and only in 6% of the patients with lcSSc (p<0.01). Joint contractures were observed in 70.9% of the patients with dcSSc and in 26.0% of the patients with lcSSc (p<0.001). Muscle weakness was noticed more frequently in patients with dcSSc (lcSSc/dcSSc: 22.0%/40.0%, p<0.05). Arthralgia was found more frequently in patients with dcSSc, but arthritis became apparent, without significant difference in frequency, in 16% of the patients with lcSSc and in 16.4% of the patients with dcSSc. Loss of capillaries (detected by nailfold capillaroscopy), digital ulcers, interstitial lung fibrosis, decreased FVC and DLCO, esophageal hypomotility, musculoskeletal impairment, and heart and renal involvement are more common in patients with dcSSc. Fingertip osteolysis, telangiectasia, and arthritis are equally frequent in both forms of the disease.     

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.     

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.     

系统性硬化症相关间质性肺疾病的临床特点及危险因素分析

目的探讨系统性硬化症相关间质性肺疾病（SSc-ILD）的临床特点及危险因素。方法收集系统性硬化症（SSc）患者68例,根据有无间质性肺疾病（ILD）分为SSc-ILD组（44例）和单纯SSc组（24例）,分析SSc-ILD患者临床表现、自身抗体、胸部CT、肺功能及超声心动图特点,并与单纯SSc组比较。结果 SSc-ILD组中弥漫性皮肤损害型SSc（dcSSc）21例、局限性皮肤损害型SSc（lcSSc）23例,有呼吸系统表现者34例,其中活动后胸闷/气短30例、干咳18例。抗Scl-70抗体在SSc-ILD和dcSSc中的阳性率分别高于单纯SSc和lcSSc。SSc-ILD最常见的胸部CT表现为磨玻璃影（25例）,其次为网格状影（19例）。28例SSc-ILD行肺功能检测,其中弥散功能减退24例、限制性通气功能障碍13例。8例单纯SSc出现弥散功能减退,其中6例行超声心动图检查,5例有肺动脉高压（PAH）。SSc患者PAH发生率为58.93%（33/56）,ILD同时合并PAH者23例。结论 SSc-ILD以活动后胸闷/气短、磨玻璃影和弥散功能减退常见。单纯SSc若出现弥散功能减退,需警惕PAH可能。dcSSc及抗Scl-70抗体阳性是SSc发生ILD的危险因素。     

Health values of patients with systemic sclerosis

OBJECTIVE: To assess health values in subjects with systemic sclerosis (SSc) and determine variability explained by demographics, clinical factors, health status, and disease severity. METHODS: We interviewed 107 individuals with SSc who attended national and local Scleroderma Foundation meetings in 2005. Health status was measured using the Short Form 36 (SF-36) Physical Component Summary (PCS; range 0-100) and Mental Component Summary (MCS; range 0-100), the Center for Epidemiologic Studies Depression Scale (CES-D; range 0-60), and the Health Assessment Questionnaire (HAQ) disability index (DI; range 0-3). Disease severity was assessed using a visual analog scale (VAS; range 0-150). Health value measures included the 0-100 health rating scale (RS), standard gamble (SG; range 0.0-1.0), and time trade-off (TTO; range 0.0-1.0). We performed univariate analyses to compare scores between participants with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc), and multivariable analyses for 3 outcome measures: RS, SG, and TTO, controlling for demographics, type of SSc, health status, and disease severity. RESULTS: Of the 107 participants, 48 had dcSSc and 59 had lcSSc. Ninety-seven were women and 83 were white. The median scores for the PCS, MCS, and HAQ DI were 36.9, 45.5, and 0.9, respectively. Fifty-five subjects had significant depressive symptoms (CES-D score >or=16). The median RS, SG, and TTO scores were 62, 0.83 (indicating a willingness to accept up to a 17% risk of immediate death in exchange for perfect health), and 0.88 (indicating a willingness to give up a median of 12% of life expectancy in exchange for perfect health), respectively. Subjects with dcSSc had lower RS scores but higher SG scores (corresponding to a willingness to accept only a smaller risk of death) than subjects with lcSSc. TTO scores were similar in the 2 groups. Health values were variably related to factors such as demographics, VAS score, disease classification, and SF-36 PCS and MCS scores (R(2) = 0.22, 0.23, and 0.66 for the SG, TTO, and RS models, respectively). CONCLUSION: Individuals with dcSSc have lower health ratings but higher SG health values than individuals with lcSSc. These findings have implications for decision analysis and cost-effectiveness analysis.     

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.     

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 significance of serum levels of matrix metalloproteinase-13 in patients with systemic sclerosis

OBJECTIVES: To investigate the clinical significance of serum matrix metalloproteinase-13 (MMP-13) levels in patients with systemic sclerosis (SSc). METHODS: Serum MMP-13 levels were determined by using a peptide substrate cleavage assay in 20 patients with diffuse cutaneous SSc (dcSSc), 20 with limited cutaneous SSc (lcSSc) and 10 normal controls. RESULTS: The serum MMP-13 levels in patients with dcSSc or lcSSc were significantly lower than those in normal controls (53.4 +/- 14.1 vs 73.2 +/- 11.5 ng/ml, P < 0.0005; 59.4 +/- 14.8 vs 73.2 +/- 11.5 ng/ml, P < 0.005, respectively), but there was no significant difference in the serum MMP-13 levels between patients with dcSSc and those with lcSSc. Disease duration prior to the diagnosis was significantly shorter in SSc patients with decreased serum MMP-13 levels than in those with normal levels (3.0 +/- 2.2 vs 8.6 +/- 7.6 yr, P < 0.0005). In addition, serum MMP-13 levels were moderately correlated with the duration of the disease (r = 0.451, P < 0.05). Though there was no significant difference in the frequencies of pulmonary fibrosis or reduced %DLco (diffusing capacity of lung for carbon monoxide), the frequency of reduced %VC (vital capacity) was significantly greater in patients with decreased serum MMP-13 levels than in those with normal levels (73 vs 24%, P < 0.05). CONCLUSIONS: Matrix metalloproteinase-13 may be involved in the fibrotic process of SSc, especially in the initiation of fibrosis. The serum MMP-13 levels may serve as a useful marker for the severity of pulmonary fibrosis in patients with SSc.     

Clinical risk assessment of organ manifestations in systemic sclerosis: a report from the EULAR Scleroderma Trials And Research group database

BACKGROUND: Systemic sclerosis (SSc) is a multisystem autoimmune disease, which is classified into a diffuse cutaneous (dcSSc) and a limited cutaneous (lcSSc) subset according to the skin involvement. In order to better understand the vascular, immunological and fibrotic processes of SSc and to guide its treatment, the EULAR Scleroderma Trials And Research (EUSTAR) group was formed in June 2004. AIMS AND METHODS: EUSTAR collects prospectively the Minimal Essential Data Set (MEDS) on all sequential patients fulfilling the American College of Rheumatology diagnostic criteria in participating centres. We aimed to characterise demographic, clinical and laboratory characteristics of disease presentation in SSc and analysed EUSTAR baseline visits. RESULTS: In April 2006, a total of 3656 patients (1349 with dcSSc and 2101 with lcSSc) were enrolled in 102 centres and 30 countries. 1330 individuals had autoantibodies against Scl70 and 1106 against anticentromere antibodies. 87% of patients were women. On multivariate analysis, scleroderma subsets (dcSSc vs lcSSc), antibody status and age at onset of Raynaud's phenomenon, but not gender, were found to be independently associated with the prevalence of organ manifestations. Autoantibody status in this analysis was more closely associated with clinical manifestations than were SSc subsets. CONCLUSION: dcSSc and lcSSc subsets are associated with particular organ manifestations, but in this analysis the clinical distinction seemed to be superseded by an antibody-based classification in predicting some scleroderma complications. The EUSTAR MEDS database facilitates the analysis of clinical patterns in SSc, and contributes to the standardised assessment and monitoring of SSc internationally.     

Pulmonary arterial hypertension is a major mortality factor in diffuse systemic sclerosis, independent of interstitial lung disease

OBJECTIVE: To determine whether pulmonary arterial hypertension (PAH) is a prognostic factor for mortality in diffuse cutaneous systemic sclerosis (dcSSc), independent of interstitial lung disease (ILD). METHODS: ILD was diagnosed by high-resolution computed tomography and PAH (pulmonary arterial systolic pressure [PASP] > or =45 mm Hg) by echocardiography. All patients with ILD underwent testing for total lung capacity (TLC), forced vital capacity (FVC), and diffusing capacity for carbon monoxide. RESULTS: Eighty-six patients with dcSSc (mean age at diagnosis 44.5 years) were followed up for a median of 72.5 months. ILD was found in 52 patients (60%) and PAH in 18 (21%). ILD was associated with PAH in 15 patients. Seventeen patients died (19.8%), 9 of whom had PAH (P = 0.001) and 10 of whom had ILD (P = 0.99). By multivariate analysis, age at SSc diagnosis and PAH were the only independent predictors of death (hazard ratio [HR] 1.057, 95% confidence interval [95% CI] 1.009-1.109, P = 0.020 and HR 4.09, 95% CI 1.47-11.5, P = 0.007, respectively). Mean TLC and mean FVC were similar in ILD patients with and those without PAH (P = 0.71 and P = 0.40, respectively). Among ILD patients, age at SSc diagnosis and PAH were again the sole predictors of death (HR 1.073, 95% CI 1.003-1.149, P = 0.042 and HR 5.07, 95% CI 1.09-23.8, P = 0.038, respectively). Twenty ILD patients received at least 6 monthly pulses of intravenous cyclophosphamide (CYC). In CYC-treated patients with PAH (n = 8), PASP increased significantly during the CYC regimen (mean +/- SD 55 +/- 14.5 mm Hg; P = 0.015 versus baseline), while TLC remained stable during the same period. CONCLUSION: These results indicate that, independent of ILD, PAH is a major prognostic factor for survival in dcSSc.     

Use of antibodies recognizing cyclic citrullinated peptide in the differential diagnosis of joint involvement in systemic sclerosis

Objective: To determine the prevalence of anti-cyclic citrullinated peptide (CCP) antibodies in systemic sclerosis (SSc) and to assess any association between the presence of anti-CCP, radiographic features, and clinical manifestations. Materials and methods: Anti-CCP antibodies and rheumatoid factor (RF) were tested in serum samples from 75 patients with SSc (64 women and 11 men), with a mean age of 59.4 years (range 24–85) with either diffuse (dcSSc) and limited (lcSSc) cutaneous involvement. As a control group, 22 age- and sex-matched healthy controls (HCs) were examined. Standard radiographs of the hands and wrists were examined in each patient. Results: The presence of anti-CCP was found in sera of 10.6% (8/75) patients with SSc (lcSSc 3 of 44, 6.8%; dcSSc 5 of 31, 16.1%). None of the HCs was positive for anti-CCP. The positivity of RF was observed in 19 of 75 (25.3%) SSc patients (lcSSc 10 of 44, 22.7%; dcSSc 9 of 31, 29%). Statistically significant association was found between anti-CCP positivity and the presence of arthritis (p<0.0001) and marginal erosions (p=0.001). Conclusion: Our data show that joint involvement is a common presenting feature of SSc. In this report, we show that anti-CCP antibodies can be detected also in patients with SSc, but they are generally less commonly present than in adults with rheumatoid arthritis (RA). Thus, the finding of high titers of anti-CCP antibodies may help to define the diagnosis of overlap syndrome SSc/RA and facilitate diagnosis and appropriate treatment.     

Non-invasive measurement of biomechanical skin properties in systemic sclerosis

OBJECTIVE: To evaluate biomechanical properties of skin in patients with systemic sclerosis (SSc) using the BTC-2000 suction device. METHODS: Twenty five patients with limited cutaneous SSc (lcSSc), 20 patients with diffuse disease (dcSSc), and 25 age matched healthy controls were evaluated. Viscoelastic deformation (VED, mm), elastic deformation (ED, mm), ultimate deformation (UD, mm), and pressure-deformation ratio (PDR, mm Hg/mm) were measured on the dorsal surface of the forearm, shoulder, and above the trapezius muscle on the back. RESULTS: Indices of skin extensibility (VED, ED, UD) were reduced and resistance to stress (PDR) increased in patients with dcSSc compared with healthy controls, or patients with lcSSc, at all three sites (p<0.001). At all sites, and overall, UD, ED, and VED were lower and PDR was higher at skin score above grade 2, compared with clinically normal skin. For both lcSSc and dcSSc biomechanical differences from controls were found even at sites of clinically normal skin. CONCLUSION: BTC-2000 is a sensitive tool for clinical evaluation of skin involvement in SSc and may be a valuable adjunct to skin sclerosis score in disease monitoring.     

Red blood cell distribution width as a related factor of pulmonary arterial hypertension in patients with systemic sclerosis

The aim of this study was to investigate the utility of red blood cell distribution width (RDW) as a simple and readily available marker of occurrence of pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc). One hundred and forty-five consecutive patients with SSc were recruited to the single-center cross-sectional study. Demographic characteristics, hematological parameters, Modified Rodnan Skin Score, and World Health Organization functional classification were determined. Diagnosis of PAH was based on screening by echocardiography and was confirmed by right heart catheterization. Interstitial lung disease (ILD) was diagnosed based on chest high-resolution computed tomography findings. There were no significant differences in gender, age, or disease duration between limited and diffused SSc groups. PAH was detected in 28 of lcSSc (33.3%) and 14 of dcSSc (23.0%) subjects. Patients with higher RDW values were more likely to be men with high anti-u1RNP titers and PAH. A significant correlation was found between RDW and high-sensitivity C-reactive protein (p?=?0.375, p?<?0.01) and the diffusing capacity of the lungs for carbon monoxide (ρ?=???0.396, p?<?0.01). The SSc-PAH group had significantly higher RDW values compared to the SSc group without pulmonary disease (15.7?±?2.2 and 13.7?±?1.0, p?<?0.001). The mean RDW in the SSc-PAH-ILD group was significantly higher than that in the SSc-ILD group (16.3?±?2.2% and 14.0?±?1.5%, p?<?0.001). Besides the recognized risk factors, high RDW was an independent predictor of PAH in patients with SSc (OR?=?3.314 [95%CI 1.038–10.580], p?<?0.05). RDW may be a related factor for identifying the pulmonary arterial hypertension in SSc patients.