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Background: Most Thai patients with systemic sclerosis (SSc) have diffuse cutaneous SSc (dcSSc) unlike most Caucasians and some Asians. A longitudinal cohort study among Thai dcSSc is needed., Objectives: We aimed to determine the overall clinical characteristics, define the clinical difference between limited cutaneous SSc (lcSSc) and dcSSc, and ascertain the mortality rate and the factors associated with mortality., Method: We conducted a cohort study including 566 Thai adult SSc patients between January 2013 and June 2019. Clinical difference between lcSSc and dcSSc was investigated using generalized estimating equations (GEE)., Results: Females presented more than males (356 vs 210 cases). The majority of cases were dcSSc (411; 72.6%). The median duration of disease at the time of pulmonary fibrosis (PF) detection was 2.5 years, pulmonary arterial hypertension 8.1 years, and renal crisis 4.1 years. By GEE analysis, dcSSc was significantly associated with salt-and-pepper skin, hand deformity, and every 1-point increase in modified Rodnan skin score (mRSS). A greater mortality risk was associated with age at onset >60 years (hazards ratio [HR] 5.5), a World Health Organization functional class (FC) III (HR 5.1), FC IV (HR 34.8), edematous skin (HR 11.4), early onset of PF (HR 1.7), each 5-point increase in the mRSS (HR 4.5), and ≥2 internal organ involvements (HR 10.1)., Conclusion: dcSSc is a common SSc subset among Thais. PF was an early complication in SSc and earlier PF detection was associated with a poorer prognosis. Elderly onset, high FC, severe skin tightness, and multiple organ involvements were associated with a greater mortality risk., (© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Introduction: Systemic sclerosis (SSc) is a multisystemic autoimmune disease. Few studies have focused on the outcomes of SSC patients who require intensive care unit (ICU) admission, largely due to the absence of protocols for the optimal management of this disease during an ICU stay., Objectives: This study aimed to describe the outcomes of a series of SSc patients admitted to the ICU at a single center in Cali, Colombia., Methods: Case series of SSc patients admitted to the ICU were reviewed. The main outcome was ICU mortality. Statistical analysis was performed with measures of central tendency and proportions., Results: All the patients (n = 14) were female and either middle-aged or elderly; 9 (64%) were diagnosed with diffuse cutaneous sclerosis, and the remaining 5 patients with limited cutaneous sclerosis. Some were readmitted; therefore, the total number of ICU admissions was 21. The principal causes of ICU admissions were non-SSc-related causes (n = 15 [71.4%]). The respiratory system was the most involved on ICU admissions. The ICU mortality rate was 43% (n = 6)., Conclusions: The severity of the disease at ICU admission and comorbidity are independently associated with ICU-related mortality. Furthermore, the optimal management of SSc patients includes accurate detection of SSc-associated organ involvement. More studies involving this category of patients are needed to establish the best effective protocols.

Objectives: To evaluate the clinical characteristics of patients with interstitial lung disease (ILD) in the setting of a large cohort of systemic sclerosis (SSc) patients, and to analyse the differences according to the SSc subtype (following the modification of classification criteria of the American College of Rheumatology for SSc proposed by LeRoy and Medsger), factors are associated with moderate-to-severe impairment of lung function, as well as mortality and causes of death., Methods: A descriptive study was performed, using the available data from the Spanish Scleroderma Study Group., Results: Twenty-one referral centers participated in the registry. By April 2014, 1374 patients with SSc had been enrolled, and 595 of whom (43%) had ILD: 316 (53%) with limited cutaneous SSc (lcSSc), 240 (40%) with diffuse cutaneous SSc (dcSSc), and 39 (7%) with SSc sine scleroderma (ssSSc). ILD in the lcSSc and the ssSSc subsets tended to develop later, and showed a less impaired forced vital capacity (FVC) and a ground glass pattern on high-resolution computed tomography (HRCT) less frequently, compared with the dcSSc subset. Factors related to an FVC < 70% of predicted in the multivariate analysis were: dcSSc, positivity to anti-topoisomerase I antibodies, a ground glass pattern on HCRT, an active nailfold capillaroscopy pattern, lower DLco, older age at symptoms onset, and longer time between symptoms onset and ILD diagnosis. Finally, SSc-associated mortality and ILD-related mortality were highest in dcSSc patients, whereas that related to pulmonary arterial hypertension was highest in those with lcSSc-associated ILD., Conclusions: Our study indicates that ILD constitutes a remarkable complication of SSc with significant morbidity and mortality, which should be borne in mind in all three subgroups (lcSSc, dcSSc, and ssSSc).

Objective: LcSSc is associated with ACAs and a mild course, whereas dcSSc is associated with anti-topoisomerase antibodies (ATAs) and a more severe course. However, ATAs are also present in lcSSc. Little is known about survival and organ involvement in this subgroup. The aim of this study is to determine whether survival and organ involvement of lcSSc ATA-positive patients differs from lcSSc ATA-negative or dcSSc ATA-positive patients. Furthermore, transition from lcSSc to dcSSc was evaluated., Methods: Data from The Nijmegen Systemic Sclerosis cohort were used, with up to 15 years of follow-up. Kaplan-Meier analysis was performed for survival and organ involvement, including interstitial lung disease, pulmonary arterial hypertension, cardiac involvement and Scleroderma Renal Crises. Cox proportional hazard modelling was performed to adjust for confounders., Results: A total of 460 patients were included: 58 (13%) lcSSc ATA-positive patients, 237 (52%) lcSSc ATA-negative patients and 78 (17%) dcSSc ATA-positive patients. Cumulative survival in lcSSc ATA-positive patients was 75%, in lcSSc ATA-negative patients 58% and in dcSSc ATA-positive patients 53%. Interstitial lung disease was more prevalent in lcSSc ATA-positive patients (49%) than in lcSSc ATA-negative patients (25%), but less than in dcSSc ATA-positive patients (60%). Forty-eight patients developed dcSSc: 24 ATA-negative and 24 ATA-positive (P < 0.001)., Conclusion: LcSSc ATA-positive patients differ from lcSSc ATA-negative patients and dcSSc ATA-positive patients concerning survival and organ involvement. LcSSc patients who are ATA-positive are more likely to develop dcSSc than lcSSc patients who are ATA negative., (© The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

In chronic heart failure (CHF) due to systemic cardiovascular disease, obese patients have better survival. Bodyweight versus survival was analyzed post hoc in subjects with limited scleroderma (SSc) and isolated pulmonary artery hypertension (PAH), i.e. with CHF due to pulmonary vascular disease. Rheumatologists referred scleroderma subjects for evaluation, and PAH was ascertained by right heart catheterization (RHC). Forty-nine SSc-PAH subjects were stratified by body mass index (BMI): obese 7 (14.3 %), overweight 11 (22.4 %), normal weight 21 (42.9 %), and underweight 10 (20.4 %) for 24-month follow-up and pooled together for long-term 72-month follow-up. Survival was analyzed by Kaplan-Meier method. Multivariate Cox proportional hazards modeling helped to assess variables associated to survival. At 24 months (17 events), survival increases with BMI across four groups (logrank for trend P = 0.031). By Cox multivariate mortality, best model included: BMI (P = 0.043), low lung diffusion (DLco, P = 0.007), and reduced stroke volume index (SVI, P = 0.017). At 72 month (37 events), higher BMI values were associated with better survival but not significantly (P = 0.076). By multivariate modeling BMI did not enter any model, whereas low DLco entered all (P < 0.001). Also low SVI (P = 0.02) and low mixed venous saturation (SvO2, P = 0.009) were associated with the prognosis. From PAH diagnosis to final event, BMI had small (5.4 %), but significant decline (P < 0.001). This is ascribed to CHF progression, and may explain BMI predictive power weakening. The results suggest BMI decline should be contrasted, DLco is useful for screening and with SVI and SvO2 for assessing prognosis and treatment.

Background: Autologous haemopoietic stem-cell transplantation (HSCT) benefits patients with systemic sclerosis but has been associated with significant treatment-related mortality and failure to improve diffusion capacity of carbon monoxide (DLCO). We aimed to assess efficacy of HSCT and use of rigorous cardiac screening in this group., Methods: We assessed patients with diffuse systemic sclerosis or limited systemic sclerosis and interstitial lung disease who were treated with HSCT as part of a study or on a compassionate basis at Northwestern University (Chicago, IL, USA) or the University of São Paulo (Ribeirão Preto, Brazil). Unselected peripheral blood stem cells were harvested with cyclophosphamide (2 g/m(2)) and filgrastim. The transplant regimen was a non-myeloablative regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulin (rATG; 4·5-6·5 mg/kg). We followed patients up to 5 years for overall survival, relapse-free survival, modified Rodnan skin score, and pulmonary function tests., Findings: Five (6%) of 90 patients died from treatment-related causes. Despite standard guidelines that recommend echocardiogram for screening before transplantation, four treatment-related deaths occurred because of cardiovascular complications (one constrictive pericarditis, two right heart failures without underlying infection, and one heart failure during mobilisation), and one death was secondary to sepsis without documented underlying heart disease. Kaplan-Meier analysis showed survival was 78% at 5 years (after eight relapse-related deaths) and relapse-free survival was 70% at 5 years. Compared with baseline, we noted improvements after HSCT in modified Rodnan skin scores at 1 year (58 patients; p<0·0001), 2 years (42 patients; p<0·0001), and 3 years (27 patients; p<0·0001) and forced vital capacity at 1 year (58 patients; p=0·009), 2 years (40 patients; p=0·02), and 3 years (28 patients; p=0·004), but total lung capacity and DLCO were not improved significantly after HSCT. Overall mean DLCO was significantly improved in patients with normal baseline echocardiograms (p=0·005) or electrocardiographs (p=0·05)., Interpretation: Autologous HSCT with a non-myeloablative regimen of cyclophosphamide and rATG with a non-selected autograft results in sustained improvement in skin thickness and forced vital capacity. DLCO is affected by baseline cardiac function. Guidelines for cardiac screening of patients with systemic sclerosis to assess treatment-related risk from pulmonary artery hypertension, primary cardiac involvement, or pericardial disease should be reconsidered and updated., Funding: None., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Objective: To determine the potential clinical and pathological significance of altered expression of interleukin 6 (IL-6) in systemic sclerosis (SSc)., Methods: Serum IL-6 and soluble IL-6 receptor levels were measured in patients with SSc (n=68) and healthy controls (n=15). Associations between serum IL-6 level and C reactive protein, platelet count and key clinical outcomes in SSc were explored. Expression of IL-6 in skin biopsies was also examined and western blot and reverse transcription PCRanalysis were performed using cultured dermal fibroblasts. The effect of IL-6 trans-signalling on production of extracellular matrix proteins was assessed and downstream signalling pathways were examined using pharmacological inhibitors., Results: Serum IL-6 level was frequently elevated in patients with SSc, particularly in those with diffuse cutaneous SSc (dcSSc) with thrombocytosis and elevated acute phase markers. Prominent expression in the skin was observed in dermal fibroblasts, mononuclear cells and endothelial cells in patients with early dcSSc. In vitro experiments supported a potent profibrotic effect of IL-6 trans-signalling via the JAK2/STAT3 and ERK pathways. High IL-6 expression early in dcSSc appears to be associated with more severe skin involvement at 3 years and worse long-term survival than in those without elevated IL-6 levels., Conclusion: Our results confirm the overexpression of IL-6 in dcSSc and support the potential of IL-6 as a surrogate marker for clinical outcome in this disease. The data also provide rationale for clinical studies targeting IL-6 trans-signalling as a potential antifibrotic therapy for SSc.

Aim: To investigate the relationship between scleroderma-specific autoantibodies and clinical phenotype and survival in South Australian patients with scleroderma., Method: Two cohorts of patients were studied from the South Australian Scleroderma Register (SASR). In the first, the sera of 129 consecutive patients were analyzed for anticentromere (ACA), anti-Scl70, anti-RNA polymerase III, anti-U1RNP, anti-Th/To, anti-Pm/Scl, anti-Ku and anti-fibrillarin antibodies using the Euroline immunoblot assay. Statistical analysis was performed to look for a significant association between specific antibodies and various clinical features. In the second cohort survival from first symptom onset was analyzed in 285 patients in whom the autoantibody profile was available, including ACA, Anti-Scl70, anti-U1RNP and anti-RNA polymerase III measured using multiple methods. Survival analysis compared mortality between different groups of patients with specific antibodies., Results: ACA, Th/To and Ku antibodies were associated with limited scleroderma, Scl70 and RNA Pol III antibodies were associated with diffuse scleroderma and antibodies to U1RNP were associated with overlap syndrome. Significant associations between Scl70 and interstitial lung disease (P = 0.004), RNA Pol III and renal crisis (P = 0.002), U1RNP and pulmonary hypertension (P = 0.006) and Th/To and pulmonary hypertension (P = 0.034) were seen. Trends were observed with an increased frequency of lung disease with Pm/Scl and Th/To and an increased frequency of myositis with Ku. The presence of Scl70, RNA Pol III and U1RNP was associated with significantly reduced survival as compared with patients with ACA., Conclusions: Scleroderma-specific autoantibodies are associated with clinical phenotype and survival., (© 2011 The Authors. International Journal of Rheumatic Diseases © 2011 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd.)

Objectives: Systemic sclerosis (SSc) is a multiorgan disease with high mortality rates. Several clinical features have been associated with poor survival in different populations of SSc patients, but no clear and reproducible prognostic model to assess individual survival prediction in scleroderma patients has ever been developed., Methods: We used Cox regression and three data mining-based classifiers (Naïve Bayes Classifier [NBC], Random Forests [RND-F] and logistic regression [Log-Reg]) to develop a robust and reproducible 5-year prognostic model. All the models were built and internally validated by means of 5-fold cross-validation on a population of 558 Italian SSc patients. Their predictive ability and capability of generalisation was then tested on an independent population of 356 patients recruited from 5 external centres and finally compared to the predictions made by two SSc domain experts on the same population., Results: The NBC outperformed the Cox-based classifier and the other data mining algorithms after internal cross-validation (area under receiving operator characteristic curve, AUROC: NBC=0.759; RND-F=0.736; Log-Reg=0.754 and Cox= 0.724). The NBC had also a remarkable and better trade-off between sensitivity and specificity (e.g. Balanced accuracy, BA) than the Cox-based classifier, when tested on an independent population of SSc patients (BA: NBC=0.769, Cox=0.622). The NBC was also superior to domain experts in predicting 5-year survival in this population (AUROC=0.829 vs. AUROC=0.788 and BA=0.769 vs. BA=0.67)., Conclusions: We provide a model to make consistent 5-year prognostic predictions in SSc patients. Its internal validity, as well as capability of generalisation and reduced uncertainty compared to human experts support its use at bedside. Available at: http://www.nd.edu/~nchawla/survival.xls.

Purposes: To evaluate the pathologic patterns, clinical features, and survival among subjects with scleroderma (ie, systemic sclerosis [SSc]) and clinically significant interstitial lung disease (ILD) evaluated at an ILD center., Methods: Retrospective cohort study of all SSc patients who had been referred for further evaluation of ILD and had undergone surgical lung biopsy. Clinical data were abstracted by review of the medical record, and lung biopsy specimens were reviewed and classified according to current pathologic criteria., Results: All patients presented with significant respiratory symptoms. Twenty-two of 27 subjects had surgical lung biopsy-proven ILD, and 5 subjects had miscellaneous non-ILD patterns. Of those subjects with ILD, 64% (14 of 22 subjects) had a nonspecific interstitial pneumonia (NSIP) pathologic pattern (fibrotic NSIP, 13 subjects; cellular NSIP, 1 subject), and 36% (8 of 22 subjects) had the usual interstitial pneumonia (UIP) pattern. Subjects with NSIP were younger (median age, 42 vs 58 years, respectively; p = 0.003), but no differences were noted in pulmonary physiology (FVC: NSIP group, 52% predicted; UIP group, 65% predicted; p = 0.22; diffusing capacity of the lung for carbon monoxide: NSIP group, 40% predicted; UIP group, 42% predicted; p = 1.0). All patients had limited skin involvement. The Scl-70 antibody was absent among those assessed (NSIP group, 0 of 10 subjects; UIP group, 0 of 7 subjects). All patients were treated with cytotoxic therapy. The median survival time for those with NSIP was 15.3 years (5,596 days) compared with 3 years (1,084 days) for those with UIP (p = 0.07 [log-rank test])., Conclusions: In SSc patients with limited cutaneous disease and clinically significant ILD, fibrotic NSIP and UIP are the predominant pathologic patterns. Those with the UIP pattern of disease had a trend toward shorter survival time.

Systemic sclerosis is a rare and potentially devastating connective tissue disease. It is highly heterogeneous in terms of clinical presentation, extent and severity of organ involvement, immunologic abnormalities, and clinical course. Although clinical outcomes appear to have improved in recent years, the disease continues to cause substantial excess mortality. In this review, we have systematically collected the published studies addressing the mortality burden in patients with scleroderma in comparison with the general population, as well as studies exploring the most important potential predictors of mortality. Results of these studies are presented and discussed, with emphasis on methodological limitations. Suggestions are made for the design, conduct, and reporting of further research on these themes.

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.

Objective: Pulmonary arterial hypertension related to scleroderma (PAH-Scl) is associated with high morbidity and mortality as well as poorer response to therapy and worse outcomes compared with the idiopathic form of PAH (IPAH). Scleroderma is an autoimmune disease that can affect left and right heart function directly through inflammation and fibrosis and indirectly through systemic and pulmonary hypertension. This study tested the hypothesis that an increased prevalence of left heart disease might explain the higher mortality in patients with PAH-Scl compared with patients with IPAH., Methods: The study was designed as a retrospective cohort study comparing the baseline clinical data from 91 consecutive patients (41 with IPAH and 50 with PAH-Scl). Cox proportional hazards models were used to predict the effect of clinical covariates on patient survival., Results: Patients with PAH-Scl had a lower mean pulmonary artery pressure (46.6 mm Hg versus 54.4 mm Hg in patients with IPAH; P = 0.002) despite similar levels of cardiac dysfunction (cardiac index 2.2 and 2.1 liters/minute/m(2), respectively; P = 0.19). Echocardiography revealed similar degrees of right ventricular dysfunction in the 2 groups, whereas a predominance of left heart dysfunction was observed in patients with PAH-Scl. One- and three-year survival estimates were 87.8% and 48.9%, respectively, in patients with PAH-Scl and 95.1% and 83.6%, respectively, in those with IPAH. Patients with PAH-Scl were 3.06 times more likely to die than were patients with IPAH, after controlling for the presence of pericardial effusion; there was no significant change in increased risk of death in PAH-Scl after controlling for left heart disease., Conclusion: The results confirm that there are significant clinical and survival differences between IPAH and PAH-Scl. The presence of left heart disease, although more common in PAH-Scl, was not predictive of the higher mortality in these patients.

Objective: Reported associations between HLA alleles and both susceptibility to and features of scleroderma have been conflicting. Our objective was (1) to determine the role of HLA alleles in the susceptibility to scleroderma; and (2) to determine the role of HLA alleles in various aspects of disease expression., Methods: Consecutive patients were followed in the scleroderma clinic between 1996 and 1998. Clinical data were obtained through chart review. Healthy volunteers as well as cadaveric donors served as controls. Molecular HLA typing was performed (polymerase chain reaction/sequence-specific oligonucleotides). Statistical analysis included Fisher's exact test and multivariate analyses, using logistic and linear regression models., Results: Ninety-five Caucasian patients (75 women, 20 men, age 43.9 yrs, disease duration 11.9 yrs) with scleroderma and 416 controls were studied. HLA-DRB1*01 and HLA-DRB1*11 were associated with susceptibility to scleroderma, whereas HLA-DRB1*07 was protective. HLA-A*30 and HLA-A*32 were also associated with susceptibility to scleroderma, while HLA-B*57 and HLA-Cw*14 were protective. HLA-B*62 and HLA-DRB1*07 had a significant correlation with the presence of diffuse skin involvement in both univariate and multivariate analyses. HLA-DRB1*11 was associated with high skin score values, while lower values were related to the presence of HLA-Cw*14 and HLA-DQB1*06. Both alleles retained significance in a linear regression model. High skin score values were related to the absence of anticentromere antibodies. Pulmonary fibrosis was associated with HLA-B*62 and HLA-Cw*0602, whereas pulmonary hypertension was associated with HLA-B*13 and HLA-B*65., Conclusion: HLA alleles play a role in susceptibility to scleroderma and its disease expression.

Background: Isolated pulmonary hypertension (PHT) is now the most frequent cause of disease-related death in limited cutaneous scleroderma, the commonest disease variant of this disabling connective tissue disorder. Endothelin-1 receptor antagonists provide symptomatic benefit but to date have not been shown to prolong survival., Aim: To determine the frequency, disease characteristics and survival of symptomatic patients with isolated PHT in our cohort of scleroderma patients., Methods: Systematic review of the clinical course of all patients registered on the South Australian Scleroderma Register, a population-based register of 374 living and 234 deceased patients with scleroderma., Results: Thirty-four patients were identified with isolated PHT, the majority with limited scleroderma. From our deceased register, we estimate that >11% of patients with this limited variant will develop this complication. Isolated PHT occurs as a late-stage complication approximately 20 years after the first symptoms of scleroderma. Patients with isolated PHT were characterized by the presence of multiple telangiectasia, reduced nailfold capillary density, digital ulceration, gross reduction of diffusing capacity for carbon monoxide and echocardiographic evidence of elevated pulmonary artery pressure. Survival was significantly shortened as compared with those patients without this complication (P=0.002), with a mean survival of 2.5 years from symptomatic onset of PHT., Conclusion: Isolated PHT occurs as a late-stage complication in > or =11% of patients with limited cutaneous scleroderma and leads to rapid death from right heart failure. The early use of endothelin-1 receptor antagonists may change the natural history of this fatal complication.