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Importance: Systemic sclerosis (SSc) sine scleroderma (ssSSc) is a subset of SSc defined by the absence of skin fibrosis. Little is known about the natural history and skin manifestations among patients with ssSSc., Objective: To characterize the clinical phenotype of patients with ssSSc compared with patients with limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) within the EUSTAR database., Design, Setting, and Participants: This longitudinal observational cohort study based on the international EUSTAR database included all patients fulfilling the classification criteria for SSc assessed by the modified Rodnan Skin score (mRSS) at inclusion and with at least 1 follow-up visit; ssSSc was defined by the absence of skin fibrosis (mRSS = 0 and no sclerodactyly) at all available visits. Data extraction was performed in November 2020, and data analysis was performed from April 2021 to April 2023., Main Outcomes and Measures: Main outcomes were survival and skin manifestations (onset of skin fibrosis, digital ulcers, telangiectasias, puffy fingers)., Results: Among the 4263 patients fulfilling the inclusion criteria, 376 (8.8%) were classified as having ssSSc (mean [SD] age, 55.3 [13.9] years; 345 [91.8%] were female). At last available visit, in comparison with 708 patients with lcSSc and 708 patients with dcSSc with the same disease duration, patients with ssSSc had a lower prevalence of previous or current digital ulcers (28.2% vs 53.1% in lcSSc; P < .001; and 68.3% in dcSSc; P < .001) and puffy fingers (63.8% vs 82.4% in lcSSc; P < .001; and 87.6% in dcSSc; P < .001). By contrast, the prevalence of interstitial lung disease was similar in ssSSc and lcSSc (49.8% and 57.1%; P = .03) but significantly higher in dcSSc (75.0%; P < .001). Skin telangiectasias were associated with diastolic dysfunction in patients with ssSSc (odds ratio, 4.778; 95% CI, 2.060-11.081; P < .001). The only independent factor for the onset of skin fibrosis in ssSSc was the positivity for anti-Scl-70 antibodies (odds ratio, 3.078; 95% CI, 1.227-7.725; P = .02). Survival rate was higher in patients with ssSSc (92.4%) compared with lcSSc (69.4%; P = .06) and dcSSc (55.5%; P < .001) after up to 15 years of follow-up., Conclusions and Relevance: Systemic sclerosis sine scleroderma should not be neglected considering the high prevalence of interstitial lung disease (>40%) and SSc renal crisis (almost 3%). Patients with ssSSc had a higher survival than other subsets. Dermatologists should be aware that cutaneous findings in this subgroup may be associated with internal organ dysfunction. In particular, skin telangiectasias in ssSSc were associated with diastolic heart dysfunction.

Patients with systemic sclerosis (SSc) have some potential factors associated with an increased risk of sarcopenia. There has been currently no study to examine such associations in SSc patients. We aimed to determine the prevalence of sarcopenia among SSc patients and examine its association with clinical manifestations and laboratory tests. A cross-sectional study was conducted in 180 adult SSc patients at the Scleroderma Clinic, Khon Kaen University, Thailand, between July 2019 and April 2020. Clinical data, laboratory tests for inflammatory markers, serology, hormone, body composition by dual-energy X-ray absorptiometry, handgrip strength, functional lower extremity strength, and usual gait speed were collected and measured. Sarcopenia was defined according to the criteria of the Asian Working Group for Sarcopenia. One hundred and eighty patients were recruited. Ninety-four cases (52.2%) were the diffuse cutaneous SSc subset. The respective mean age and duration of disease was 58.8 ± 9.4 and 6.2 ± 5.3 years. Sarcopenia was revealed in 41 SSc patients for a prevalence of 22.8% (95% CI 12.1-34.8), while the prevalence was higher in patients with the diffuse cutaneous SSc (dcSSc) compared to the limited cutaneous SSc. BMI at the onset of SSc and C-reactive protein > 5 mg/dL were significantly associated with sarcopenia with a respective OR of 0.60 (95% CI 0.48-0.75) and 3.18 (1.06-9.54). Sarcopenia is common in patients with SSc, but the prevalence is more pronounced in the dcSSc. Inflammatory markers, particularly the CRP level, are strongly associated. BMI at the onset had a negative association with sarcopenia among SSc patients., (© 2022. The Author(s).)

Objective: Systemic sclerosis (SSc) is an autoimmune disease the prevalence of which varies among populations. We analyzed SSc patients from Guangxi to improve the clinical understanding of this disease., Methods: Data of 470 SSc patients admitted to our institution from October 1,2012 to January 1,2019 were examined. The characteristics of these patients were analyzed using Kaplan-Meier survival analysis. Cox proportional-hazard regression was used to identify prognostic factors., Results: The average age was 50.44 ± 12.31 years, 285 patients (60.6%) were women, 2.1% had pneumoconiosis, 58.2% had pulmonary interstitial disease (ILD), 18.7% had pulmonary hypertension (PH), and 3.6% had renal crisis. These patients had diffuse cutaneous systemic sclerosis (dcSSc, 70.2%) or limited cutaneous systemic sclerosis (29.7%), and PH and renal crisis were more common in the dcSSc group. Patients 50 years old or more had greater prevalences of ILD, PH, and musculoskeletal damage, greater positivity of laboratory biomarkers, and increased mortality (all P < .05). Seventy-four patients (15.7%) died. The non-survivors were older, had longer disease duration, had higher prevalences of ILD, restrictive ventilation dysfunction, PH, and renal crisis, and had higher levels of creatine kinase myocardial band (CK-MB), C-reactive protein, and immunoglobin A (all P < .05). Renal crisis, PH, and high CK-MB were independent risk factors for death., Conclusions: Pneumoconiosis was more common in SSc patients than the general population from this region. Our patients had a 10-year cumulative survival rate of 74.9%, higher than reported for patients from the US. Renal crisis, PH, and high CK-MB level were independent risk factors for death., (© 2021 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objectives: Acro-osteolysis is often associated with systemic sclerosis (SSc). However, the severity of acro-osteolysis and its clinical association among SSc patients is limited. Our aims were to assess the prevalence of acro-osteolysis and the clinical association with acro-osteolysis among SSc patients at early onset of the disease., Methods: A cross-sectional study of 120 newly diagnosed SSc patients with the onset of less than 4 years were evaluated on clinical characteristics and hand radiographs. Acro-osteolysis was graded on a 0-4-point scale based on the severity and the patients were subdivided into mild, moderate and severe., Results: Among all SSc patients enrolled, 62.5% were females, 56.1% dcSSc and the vast majority of them (84.1%) were positive for anti-topoisomerase I antibody (anti-topo I). The mean disease duration was 2.0±1.3 years. Acro-osteolysis was noted in 77 patients with a prevalence of 64.1% (95%CI 54.9-72.7), of which 16.7% were defined as severe acro-osteolysis. Logistic regression analysis revealed that acro-osteolysis was positively associated with anti-topo I (OR 13.96), hand deformity (OR 3.81) and dysphagia (OR 6.66), but negatively associated with oedematous skin (OR 0.05). Analysis stratified by severity of acro-osteolysis showed significant differences between subgroup in terms of the presence of digital gangrene (p=0.02), ischaemic ulcer (p=0.001), oedematous skin (p=0.001), and hand deformities (p=0.01)., Conclusions: Acro-osteolysis was common in SSc at the early onset of disease. While the presence of anti-topo I, hand deformity and esophageal involvement were strongly associated with acro-osteolysis, oedematous skin was the protective factor for acro-osteolysis.

Objective: The aim of this study is to describe 4 of the most common autoantibodies against components of the Th/To complex: human POP1 (hPOP1), RPP25, RPP30, and RPP40. We report their prevalence and clinical characteristics in a systemic sclerosis (SSc) population, and determine whether these specificities are associated with cancer., Methods: A case-control study was performed using data from the Johns Hopkins Scleroderma Center Cohort. A total of 804 adult patients with SSc were included; 401 SSc patients with no history of cancer after at least 5 years of disease were compared to 403 SSc patients who ever had a history of cancer. Antibodies against hPOP1, RPP25, RPP30, and RPP40 were assayed by immunoprecipitation of 35 S-methionine-labeled proteins generated by in vitro transcription/translation. Demographic and clinical characteristics were compared between groups., Results: Of 804 patients, 67 (8.3%) had antibodies against any component of the Th/To complex. Patients with antibodies to any component were significantly more likely to have limited cutaneous disease, less likely to have tendon friction rubs, and more likely to have findings consistent with interstitial lung disease or pulmonary hypertension. Patients with antibodies against hPOP1, RPP25, RPP30, and/or RPP40 were significantly less likely to develop cancer within 2 years of SSc onset (0% versus 11% of antibody-negative patients; P = 0.009)., Conclusion: SSc patients who produce autoantibodies to components of the Th/To complex have a clinical phenotype characterized by limited cutaneous disease and pulmonary involvement. Our findings show that the presence of any Th/To autoantibody may have a protective effect against contemporaneous cancer., (© 2020, American College of Rheumatology.)

Objective: Myocardial involvement may occur during systemic sclerosis (SSc) and can lead to impaired myocardial contraction and/or arrhythmia. Cardiac magnetic resonance imaging (MRI) is used for noninvasive characterization of the myocardium. The aim of this study was to evaluate the utility of cardiac MRI with intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) and longitudinal relaxation time (T1) sequence mapping for assessment of myocardial microvascular and interstitium impairment in SSc., Methods: In this single-center prospective cohort study, 40 consecutive patients with SSc and 20 healthy controls were assessed by cardiac MRI with IVIM DWI and T1 mapping sequences on a 3T scanning system. Images were analyzed independently by 2 assessors, and Bland-Altman plots were used to assess interreader concordance and reproducibility. Characteristics of the patients were compared according to quartiles of T1 and perfusion fraction (f-coefficient) values, using exact Cochran-Ermitage trend tests for qualitative variables and analysis of variance for quantitative variables. Kaplan-Meier cardiac events-free survival curves were plotted and compared with a log-rank test for trend., Results: T1 values were higher in SSc patients than in healthy controls, and were higher in the diffuse cutaneous SSc (dcSSc) subset (P = 0.02). Higher T1 values were associated with the immunologic pattern seen in patients with the dcSSc form (P = 0.0001), a higher modified Rodnan skin thickness score (MRSS) (P = 0.003), and a higher frequency of interstitial lung disease (P = 0.03). Moreover, higher T1 values were correlated with higher MRSS scores (r = +0.32, P = 0.04) and reduced forced vital capacity (r = -0.34, P = 0.048), and tended to be correlated with reduced total lung capacity (r = -0.30, P = 0.07). Lower f-coefficient values, as a measure of decreased tissue perfusion, were associated with less frequent use of vasodilators (P = 0.02 for angiotensin-converting enzyme inhibitors and P = 0.06 for calcium-channel blockers) and more frequent use of glucocorticoids (P = 0.02). The f-coefficients were inversely correlated with the T1 values (r = -0.31, P = 0.02). Furthermore, higher T1 values were associated with higher incidence of cardiac events (log-rank test for trend P = 0.03)., Conclusion: Increased T1 values, potentially suggesting microscopic fibrosis, were observed more frequently in patients with dcSSc, and higher T1 values were associated with interstitial lung disease and more frequent cardiac events during follow-up. The results of this study show that cardiac MRI with T1 mapping sequences and IVIM DWI may be useful in assessing myocardial involvement in patients with SSc., (© 2020, American College of Rheumatology.)

Objectives: To determine the prevalence of clinical manifestations and incidence rate of cardiopulmonary complications in a comparison between men and women with early SSc., Methods: An inception cohort of early-SSc patients at the Rheumatology Clinic, Maharaj Nakorn Chiang Mai Hospital, between January 2010 and June 2016, was used. All patients were assessed for clinical manifestations and underwent ECG, echocardiography, and HRCT at the study entry and then annually., Results: One hundred and fifteen patients (46 male, 90 dcSSc) with a mean (SD) disease duration of 11.6 months (8.8) at cohort entry were enrolled during a mean (SD) observational period of 3.8 years (1.6). At enrollment, the male group had a higher prevalence of dcSSc subtype (91.3% vs. 69.5%, p = 0.006), hypo-hyperpigmentation (84.8% vs. 65.2%, p = 0.021), myositis (26.1% vs. 10.1%, p = 0.024), and right ventricular dysfunction [RVD] (8.7% vs. 0%, p = 0.024) compared with women. At the last visit, the male group had a higher cumulative prevalence of digital ulcers (47.8% vs. 27.5%, p = 0.026), telangiectasia (93.5% vs. 69.6%, p = 0.002), joint contracture (69.6% vs. 43.5%, p = 0.006), tendon friction rub (39.1% vs. 20.3%, p = 0.027), LVEF < 50% (21.7% vs. 8.7%, p = 0.048), and RVD (34.8% vs. 7.2%, p < 0.001). The male group had a significantly higher incidence rate of RVD (8.21 vs. 1.99 per 100 person-years, p = 0.006) and interstitial lung disease [ILD] (65.25 vs. 40.36 per 100 person-years, p = 0.022) compared to women., Conclusions: In this study cohort, it was found that men with SSc had more severe clinical manifestations and higher incidence rate of RVD and ILD compared to women. Increased awareness of cardiopulmonary complications in men even in early phase of SSc is crucial., Key Points: • Male patients with SSc have more severe disease manifestations compared to women. • Even in the early phase of the disease, men were found to have higher incidence rates of right ventricular dysfunction and interstitial lung disease than women. • Increased awareness regarding cardiopulmonary complications in men with early SSc is crucial for effective management of these complications.

Objective: Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained., Methods: A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty-four clinical and serologic variables were used for clustering., Results: Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement., Conclusion: Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis., (© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.)

Background: Data on survival and prognosis factors in incident cohorts are scarce in systemic sclerosis (SStc). To describe survival, standardized mortality ratio (SMR), and prognosis factors in systemic sclerosis (SSc), we analyzed a multicenter French cohort of incident patients and performed a systematic review of the literature and meta-analysis., Methods: A multicenter, French cohort study was conducted between January 1, 2000, and December 31, 2013. Patients were followed-up until July 1, 2016. A systematic review of the literature was carried out in MEDLINE and EMBASE up to July 2017. Meta-analysis was performed using all available data on SMR and hazard ratios of prognosis factors., Results: A total of 625 patients (493 females, 446 lcSSc) were included. During the study period, 104 deaths (16.6%) were recorded and 133 patients were lost to follow-up. Overall survival rates at 1, 3, 5, and 10 years from diagnosis were 98.0%, 92.5%, 85.9%, and 71.7% respectively in the French cohort. Overall SMR was 5.73 (95% CI 4.68-6.94). Age at diagnosis > 60 years, diffuse cutaneous SSc, scleroderma renal crisis, dyspnea, 6-min walking distance (6MWD), forced vital capacity < 70%, diffusing capacity of the lungs for carbon monoxide < 70%, pulmonary hypertension (PH), telangiectasia, valvular disease, malignancy, anemia, and CRP > 8 mg/l were associated with a poorer survival after adjustment. Eighteen studies (11,719 patients) were included in the SMR meta-analysis and 36 studies (26,187 patients) in the prognosis factor analysis. Pooled SMR was 3.45 (95%CI 3.03-3.94). Age at disease onset, male sex, African origin, diffuse cutaneous SSc, anti-Scl70 antibodies, cardiac and renal involvement, interstitial lung disease, PH, and malignancy were significantly associated with a worse prognosis. Anti-centromere antibodies were associated with a better survival., Conclusions: Overall, our study highlights a high mortality rate in SSc patients and confirms previously described prognosis factors related to skin extension and organ involvement while identifying additional prognosis factors such as autoantibody status, telangiectasia, 6MWD, and valvular disease.

Objectives: Recent studies demonstrate autoantibodies are powerful tools to interrogate molecular events linking cancer and the development of autoimmunity in scleroderma. Investigating cancer risk in these biologically relevant subsets may provide an opportunity to develop personalised cancer screening guidelines. In this study, we examined cancer risk in distinct serologic and phenotypic scleroderma subsets and compared estimates with the general population., Methods: Patients in the Johns Hopkins Scleroderma Center observational cohort were studied. Overall and site-specific cancer incidence was calculated in distinct autoantibody and scleroderma phenotypic subsets, and compared with the Surveillance, Epidemiology and End Results registry, a representative sample of the US population., Results: 2383 patients with scleroderma contributing 37 686 person-years were studied. 205 patients (8.6%) had a diagnosis of cancer. Within 3 years of scleroderma onset, cancer risk was increased in patients with RNA polymerase III autoantibodies (antipol; standardised incidence ratio (SIR) 2.84, 95% CI 1.89 to 4.10) and those lacking centromere, topoisomerase-1 and pol antibodies (SIR 1.83, 95% CI 1.10 to 2.86). Among antipol-positive patients, cancer-specific risk may vary by scleroderma subtype; those with diffuse scleroderma had an increased breast cancer risk, whereas those with limited scleroderma had high lung cancer risk. In contrast, patients with anticentromere antibodies had a lower risk of cancer during follow-up (SIR 0.59, 95% CI 0.44 to 0.76)., Conclusions: Autoantibody specificity and disease subtype are biologically meaningful filters that may inform cancer risk stratification in patients with scleroderma. Future research testing the value of targeted cancer screening strategies in patients with scleroderma is needed., Competing Interests: Competing interests: TI, LC-R, AR and AAS have recently submitted a patent application entitled ’Materials and Methods for Assessing Cancer Risk and Treating Cancer'., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Introduction: Data regarding the incidence rate (IR) of cardiopulmonary involvement in comparison between late-onset SSc and early-onset SSc are limited., Objective: To compare the prevalence of clinical manifestations and the IR of cardiopulmonary involvement compared between the two subgroups., Methods: An inception cohort of SSc patients seen at the Rheumatology Clinic, Maharaj Nakorn Chiang Mai Hospital, between January 2010 and June 2016, was used. All patients were assessed for clinical manifestations and underwent electrocardiograph, echocardiography and high-resolution computed tomography at the study entry and every 12 months thereafter., Result: One hundred and fifteen patients (69 female and 90 diffuse cutaneous SSc [dcSSc]) with a mean (SD) disease duration of 11.6 months (8.8) at cohort entry were enrolled during a mean (SD) observation period of 3.8 years (1.6). Patients were classified into two groups: age ≥ 50 years (late onset) and age < 50 years (early onset). The late-onset group included 78 patients (67.8%). At enrollment, the late-onset group had higher prevalence of digital pitting scars (60.3% vs. 35.1%, P = 0.012), dry eye symptoms (17.9% vs. 2.7%, P = 0.035), and hypertension (20.5% vs. 5.4%, P = 0.037) compared to the early-onset group. In the last visit, it was found that the late-onset group had higher cumulative prevalence of joint contracture (61.5% vs. 37.8%, P = 0.017) compared to the early-onset group. The late-onset group had no significant IR of left ventricular ejection fraction < 50% (3.04 vs. 4.45 per 100 person-years, P = 0.486), right ventricular dysfunction (5.17 vs. 2.73 per 100 person-years, P = 0.269), interstitial lung disease (49.45 vs. 42.03 per 100 person-years, P = 0.462), and systolic pulmonary arterial pressure ≥ 50 mmHg (2.57 vs. 1.07 per 100 person-years, P = 0.267) compared to the early-onset group., Conclusion: Our study cohort found that digital pitting scar, xerophthalmia, hypo-hyperpigmentation, joint contracture, and hypertension are more prevalent in late-onset SSc than early-onset SSc. However, no significant differences regarding the IR of cardiopulmonary involvement between the two subgroups, the majority of which were dcSSc, in the early phase of the disease., (© 2018 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Aim: Data regarding the clinical and radiographic hand involvement in Asian patients with systemic sclerosis (SSc) are limited. Thus, we determined the prevalence of clinical and radiographic hand involvement in Thai SSc patients, comparing diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc). We also determined the factors associated with arthritis, contracture of fingers and digital ulcers., Method: SSc patients seen at the Rheumatology Clinic, Chiang Mai University, Thailand, from December 2012 to June 2013 were consecutively invited to enroll in the study. After study entry, demographic data, clinical features and hand radiographs were evaluated., Result: We studied 110 SSc patients (73 dcSSc) with mean ± SD age of 53.2 ± 9.2 years and disease duration from non-Raynaud's phenomenon of 4.9 ± 4.8 years. The prevalence of arthritis, finger contractures and digital ulcers were 10 (9.1%), 47 (42.7%), and 14 (12.7%), respectively. DcSSc patients had significantly more of the following hand complications than lcSSc patients: digital pitting scar (53.4% vs. 27.0%, P = 0.008), digital ulcer (17.8% vs. 2.7%, P = 0.032), traumatic ulcer (27.4% vs. 0%, P < 0.001), acrolysis (45.2% vs. 18.9%, P = 0.007) and flexion contracture (60.3% vs. 8.1%, P < 0.001). Radiographic finger contractures were more prevalent in the dcSSc subset. In multivariate logistic regression analysis, a positive rheumatoid factor was associated with arthritis; dcSSc, arthritis and modified Rodnan skin score (MRSS) > 18 were associated with contracture of fingers. Furthermore, hand MRSS > 4 was associated with digital ulcers., Conclusion: Our results confirm that dcSSc patients had more severe clinical hand complications than lcSSc. However, radiographic findings were similar among subgroups, except that more finger contractures were seen in dcSSc. Finally, the presence of rheumatoid factor is associated with arthritis, and high MRSS is associated with finger contractures and digital ulcers., (© 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: Autoantibody profiles in systemic sclerosis (SSc) and their relative clinical association vary between studies. The rate for being anti-topoisomerase-I (ATA) positive and the association with diffuse cutaneous the SSc subset (dcSSc) is higher among Thais than among Caucasians. The objective was to evaluate the relevance of clinical presentation, namely being positive for one or more autoantibodies among Thai SSc patients., Method: A retrospective, cohort study was performed among SSc patients over 18 years of age at Srinagarind Hospital, Khon Kaen University, Thailand, during January 2006 to December 2013. Autoantibodies comprising 13 SSc-specific antigens were evaluated using the EUROIMMUN AG (Lübeck, Germany) in order to define their clinical association(s)., Results: Two hundred and eighty-five scleroderma patients (200 female; 85 male) were included. The majority (66.7%) were dcSSc subset. ATA was the most common antibody profile in our patients (231 cases; 81.1%), followed by anti-Ro 52 (87 cases; 30.5%). Eleven of our patients (3.9%) were negative for all antibody profiles and 44 cases (15.4%) were negative for ATA and anti-centromere antibody (anti-CENP). Almost 40% (112 cases) were positive for at least two autoantibodies. There was an association between the presence of ATA and hand deformity (odds ratio [OR] 3.94; 95% CI 1.12-13.84), anti-CENP and hand deformity (OR 0.20; 95% CI 0.02-0.90), anti-Ku and scleroderma-polymyositis overlap syndrome (OR 6.58; 95% CI 2.16-19.39) and the absence of both ATA and anti-CENP with female sex (OR 2.90; 95% CI 1.12-7.51), limited cutaneous SSc subset (OR 2.70; 95% CI 1.30-5.55) and scleroderma-polymyositis overlap syndrome (OR 2.53; 95% CI 1.04-6.16). Neither ATA nor anti-CENP were associated with the SSc subset., Conclusions: ATA and anti-CENP were not helpful in differentiating the SSc subset in Thai SSc patients, albeit they were good for predicting hand function. Coexisting ATA and anti-CENP negativity were associated with less extensive skin tightness and SSc overlap syndrome., (© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Objective: To estimate the effect of disease activity, as measured by the European Scleroderma Research Group Activity Index (EScSG-AI), on the risk of subsequent organ damage in a large systemic sclerosis (SSc) cohort., Methods: Of 421 SSc patients from the Canadian Scleroderma Research Group database with disease duration of ⩽ 3 years, 197 who had no evidence of end-stage organ damage initially and available 3 year follow-up were included. Disease activity was assessed by the EScSG-AI with two variability measures: the adjusted mean EScSG-AI (the area under the curve of the EScSG-AI over the observation period) and persistently active disease/flare. Outcomes were based on the Medsger severity scale and included accrual of a new severity score (Δ ⩾ 1) overall and within organ systems or reaching a significant level of deterioration in health status., Results: After adjustment for covariates, the adjusted mean EScSG-AI was the most consistent predictor of risk across the study outcomes over 3 years in dcSSc: disease progression defined as Δ ⩾ 1 in any major internal organ, significant decline in forced vital capacity and diffusing capacity of carbon monoxide, severity of visceral disease and HAQ Disability Index worsening. In multivariate analysis, progression of lung disease was predicted solely by adjusted mean EScSG-AI, while the severity of lung disease was predicted the adjusted mean EScSG-AI, older age, modified Rodnan skin score (mRSS) and initial severity. The EScSG-AI was associated with patient- and physician-assessed measures of health status and overpowered the mRSS in predicting disease outcomes., Conclusion: Disease activity burden quantified with the adjusted mean EScSG-AI predicted the risk of deterioration in health status and severe organ involvement in dcSSc. The EScSG-AI is more responsive when done repeatedly and averaged., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com)

T-cell immunoglobulin and mucin domain 3 (TIM-3) has been thought to play a crucial role in the negative regulation of immune responses. Here, we examined the levels of serum soluble TIM-3 (sTIM-3) in patients with systemic sclerosis (SSc) and evaluated the results with respect to the clinical features of the disease. Patients with diffuse cutaneous SSc (dcSSc) had higher levels of sTIM-3 than those with limited cutaneous SSc and healthy individuals. Serum sTIM-3 levels were positively correlated with the severity of skin sclerosis in early phase dcSSc. Moreover, serum sTIM-3 levels were increased more often in patients with renal crisis and cardiac involvement than in those with normal sTIM-3 levels. These results suggest that serum sTIM-3 levels may be increased in patients with early phase dcSSc and associated with cardiac involvement and renal crisis. Measurement of serum sTIM-3 may be useful for risk stratification in the early stage of the disease., (© 2016 Japanese Dermatological Association.)

Objectives: We sought to assess employment status, risk factors for unemployment and the associations of unemployment with patients' health related quality of life (HRQoL)., Methods: All patients enrolled in a systemic sclerosis (SSc) longitudinal cohort study, completed an employment questionnaire on enrolment. Clinical manifestations were defined based on presence at the time of enrolment. Summary statistics, chi-square tests, univariate and multivariable logistic regression were used to determine the associations of various risk factors with employment., Results: Among 1587 SSc patients, 160 (20%) were unemployed at the time of cohort enrolment excluding retired patients. Of these, 63% had limited disease subtype. Mean (±SD) age at enrollment was 51.9 (±10.4) years; 13 years below the average retirement age in Australia. Mean (±SD) disease duration at recruitment was 11.1 (±10.9) years. Multivariable regression analysis revealed the presence of digital amputation (OR 3.9, 95%CI 1.7-9.1, p=0.002), diffuse disease subtype (OR 2.2, 95%CI 1.3-3.5, p-value=0.002), sicca symptoms (OR 2.7, 95%CI 1.6-4.4, p<0.001), a physical job (OR 1.8, 95%CI 1.1-3.1, p=0.03) and pulmonary arterial hypertension (OR 2.2, 95%CI 1.1-4.5, p=0.02) to be associated with unemployment. Unemployed patients had consistently poorer HRQoL scores in all domains (physical, emotional and mental health) of the SF-36 form than those who were employed., Conclusions: SSc is associated with substantial work disability and unemployment, which is in turn associated with poor quality of life. Raising awareness, identifying modifiable risk factors and implementing employment strategies and work place modifications are possible ways of reducing this burden.

Background: Systemic sclerosis (SSc) is a multiorgan autoimmune disorder characterized by sclerosis of the skin and organs as well as the presence of antinuclear autoantibodies. Several types of antinuclear autoantibodies have been described in SSc, associated with distinct disease entities and differences in prognosis., Methods: The aim of this study was to screen for the presence of antibodies reacting with RNA polymerase III (anti-RNAP3) in a large cohort of patients with SSc treated at a tertiary referral center and to evaluate correlations with disease severity., Results: Anti-RNAP3 antibodies were detected in 11 of 158 patients (7.0%). Eight of the 11 (72.7%) anti-RNAP3-positive patients had diffuse cutaneous SSc (P < 0.01). A higher modified Rodnan skin score, associated with diffuse SSc, correlated with the presence of anti-RNAP3 (P < 0.0001). The detection of anti-RNAP3 antibodies strongly correlated with the presence of renal involvement (P < 0.0001). The odds ratio of RNAP3-positive patients to develop renal involvement was 80.1 (95% CI 9.3-690.1)., Conclusions: This study demonstrates that the detection of anti-RNAP3 antibodies in patients with SSc correlates with renal crisis and severe cutaneous involvement. The possibility to detect specific antibodies with a prognostic value can lead to a better risk management of patients with SSc., (© 2015 The International Society of Dermatology.)

Objectives: To longitudinally map the onset and identify risk factors for skin sclerosis and digital ulcers (DUs) in patients with systemic sclerosis (SSc) from an early time point after the onset of Raynaud's phenomenon (RP) in the European Scleroderma Trials and Research (EUSTAR) cohort., Methods: 695 patients with SSc with a baseline visit within 1 year after RP onset were followed in the prospective multinational EUSTAR database. During the 10-year observation period, cumulative probabilities of cutaneous lesions were assessed with the Kaplan-Meier method. Cox proportional hazards regression analysis was used to evaluate risk factors., Results: The median modified Rodnan skin score (mRSS) peaked 1 year after RP onset, and was 15 points. The 1-year probability to develop an mRSS ≥2 in at least one area of the arms and legs was 69% and 25%, respectively. Twenty-five per cent of patients developed diffuse cutaneous involvement in the first year after RP onset. This probability increased to 36% during the subsequent 2 years. Only 6% of patients developed diffuse cutaneous SSc thereafter. The probability to develop DUs increased to a maximum of 70% at the end of the 10-year observation. The main factors associated with diffuse cutaneous SSc were the presence of anti-RNA polymerase III autoantibodies, followed by antitopoisomerase autoantibodies and male sex. The main factor associated with incident DUs was the presence of antitopoisomerase autoantibodies., Conclusion: Early after RP onset, cutaneous manifestations exhibit rapid kinetics in SSc. This should be accounted for in clinical trials aiming to prevent skin worsening., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Anti-topoisomerase I antibody (ATA) carries an increased risk of systemic sclerosis (SSc) internal organ involvement. There have been no published comparisons of the clinical characteristics of patients positive and negative for ATA in Thailand, where the positive rate for ATA is higher than among Caucasians., Objective: To define the clinical differences between SSc, positive versus negative, for ATA., Methods: A retrospective cohort study was performed among SSc patients over 18 at Srinagarind Hospital, Khon Kaen University, Thailand, during January 2006-December 2013. SSc-overlap syndrome was excluded., Results: Two hundred and ninety-four SSc patients were included (female : male 2.5 : 1). The majority (68.6%) were the diffuse cutaneous SSc subset (dcSSc). ATA was positive in 252 patients (85.7%), among whom 71.7% had dcSSc and 28.2% limited cutaneous SSc (lcSSc). Using a multivariate analysis, hand deformity had a significantly positive association with ATA (odds ratio [OR] 7.01; 95% CI 1.02-48.69), whereas being anti-centromere (ACA) positive had a negative association (OR 0.17; 95% CI 0.03-0.92). After doing a subgroup analysis of the SSc subset, the median duration of disease at time of pulmonary fibrosis detection among ATA positive dcSSc was significantly shorter than the ATA negative group (1.05 vs. 6.77 years, P = 0.01). Raynaud's phenomenon (RP) at onset was significantly more frequent in lcSSc sufferers who were ATA negative than those who were ATA positive (90.5% vs. 56.9%, P = 0.005)., Conclusions: A high prevalence of ATA positivity was found among Thai SSc patients and this was associated with a high frequency of hand deformity, ACA negativity, a short duration of pulmonary fibrosis in dcSSc and a lower frequency of RP in lcSSc., (© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Cholestatic liver diseases are rare diseases that often lead to cirrhosis and its consequent complications. In addition to liver-related morbidity, patients with cholestatic liver diseases often suffer from autoimmune diseases that affect several organs and tissues. The robust and efficient data collection and collaboration between hepatologists and rheumatologists have led to significant advancements in understanding the relationship between the cholestatic liver diseases and associated autoimmune diseases. In this paper, we discuss the cholestatic liver diseases (primary biliary cirrhosis, primary sclerosing cholangitis and immunoglobulin G4 associated cholangitis) and associated autoimmune diseases.

Objectives: To determine the prevalence of autoantibody negative systemic sclerosis (SSc) and to identify the clinical correlates thereof., Methods: Clinical data and sera from 874 SSc subjects were collected and autoantibodies were tested in a central laboratory using 1) indirect immunofluorescence (IIF), 2) commercially available ELISA, addressable laser bead immunoassay (ALBIA), and line immunoassay (LIA), and 3) a sensitive immunoprecipitation (IP) assay., Results: Fifteen (15; 1.7%) subjects were autoantibody negative by IIF, ELISA, ALBIA, LIA and IP, and 16 (1.8%) were antinuclear antibody (ANA) positive by IIF but otherwise negative by ELISA, ALBIA, LIA and IP. Thirty-seven (37; 4.2%) were ANA positive by IIF, autoantibody negative by commercially available immunoassays, but had autoantibodies identified by IP (including Th/To in 20). Autoantibody-negative subjects had generally less severe disease than positive subjects., Conclusions: Autoantibody-negative SSc is rare (<2%) and appears to be associated with a favourable prognosis.

Objectives: Prevalence of systemic sclerosis (SSc) and different clinical subsets varies across the world. Few data have been published on SSc patients in Latin America. Our objective was to describe a SSc cohort in Argentina and to compare clinical findings, disease subsets and antibodies with other international SSc populations., Methods: Patients with SSc (n=234) seen at the Rheumatology section of the Hospital Italiano de Buenos Aires between 2000-2011 were retrospectively analysed. Data on clinical manifestations, disease subsets and antibodies were obtained. Patients were classified into diffuse cutaneous (dc) and limited cutaneous (lc) subsets. Comparison with other cohorts (France, United States, Germany, Italy, Mexico, EUSTAR and Brazil) was made based on published information., Results: A higher female:male ratio (12:1) and a higher limited subset prevalence (76.1%) was found in this Argentine cohort comparing with others. We also found a lower prevalence of diffuse disease, anti Scl-70 (antitopoisomerase) and nucleolar pattern antinuclear antibodies. Within each subset, clinical findings were similar with other SSc populations except for a very low prevalence in renal crisis (0.02% of dc SS)., Conclusions: With slight variations perhaps due to genetic, environmental or referral factors, SSc in this cohort appears to be similar to that described in other parts of the world.

Objective: To describe the clinical and serological features of systemic sclerosis sine scleroderma (ssSSc) in a multicentered SSc cohort., Methods: Data from 1417 subjects in the Canadian Scleroderma Research Group registry were extracted to identify subjects with ssSSc, defined as SSc diagnosed by an expert rheumatologist, but without any sclerodactyly or skin involvement prior to baseline study visit or during followup. Clinical and serological features of ssSSc subjects were compared to limited (lcSSc) and diffuse cutaneous SSc (dcSSc) subjects., Results: At the first registry visit, only 57 subjects (4.0%) were identified as having ssSSc. Of these, 30 (2.1%) were reclassified as lcSSc within 1.9 years. Thus, only 27 ssSSc subjects (1.9%) remained, with mean followup of 2.4 years. Clinical profiles of ssSSc were generally similar or milder compared to lcSSc, and milder than dcSSc, including rates of interstitial lung disease (25.9% ssSSc, 25.4% lcSSc, 40.3% dcSSc). Patients with ssSSc had serological profiles similar to those with lcSSc, including high rates of anticentromere antibodies (50.0% ssSSc, 47.5% lcSSc, 12.1% dcSSc), and low rates of antitopoisomerase I (16.7% ssSSc, 7.0% lcSSc, 21.8% dcSSc) and anti-RNA polymerase III (0 ssSSc, 11.1% lcSSc, 34.9% dcSSc)., Conclusion: The condition ssSSc is rare and resembles lcSSc. These observations suggest that ssSSc is most likely a forme fruste of lcSSc, and that the absence of skin involvement may in part be related to misclassification arising from early or subtle skin involvement. There is little evidence to consider ssSSc as a distinct clinical or serological subset of SSc.

After immunosuppressive-induced infections, interstitial lung disease (ILD) is one of the most serious pulmonary complications associated with connective tissue diseases (CTD). Although it is common for ILD to be diagnosed concurrent with or after CTD, some patients will present with ILD years prior to receiving a diagnosis of CTD. The clinical approach involves an examination of the extrathoracic symptoms (suggestive of CTD) and the evaluation of respiratory disability. Nonspecific interstitial pneumonia is the most common histological finding in patients with CTD. The management of patients with CTD-associated ILD is optimized by multidisciplinary collaboration. ILD-CTD are treated through anti-inflammatory medication, immunosuppressants and biological agents.

Objective: Systemic sclerosis (SSc) is associated with a reduction in life expectancy, but there are no validated prognostic models for determining short-term mortality. The objective of this study was to derive and validate a prediction rule for 2-year mortality in patients with early diffuse cutaneous SSc (dcSSc)., Methods: We studied a prospectively enrolled cohort of 387 US Caucasian patients with early dcSSc (<2 years from the appearance of the first symptom), randomly divided into a derivation cohort (n = 260) and a validation cohort (n = 127). Predefined baseline predictor variables were analyzed in a stepwise multivariable logistic regression model in order to identify factors independently associated with 2-year all-cause mortality using a cutoff of P < 0.05. We rounded the beta values to the nearest integer and summed the points assigned to each variable in order to stratify patients into low-risk, moderate-risk, and high-risk groups. We then applied this rule to an external validation cohort of 110 Caucasian patients with early dcSSc from a single UK center and compared stratum-specific mortality using chi-square statistics., Results: Four independent predictor variables (with assigned integer values) comprised the model: age at first visit (points allotted: -1, 0, or 1), skin thickness progression rate (points allotted: 0 or 1), gastrointestinal tract severity (points allotted: 0, 1, or 2), and anemia (points allotted: 0 or 2). The prediction model performed well, with no significant differences between the derivation cohort and the US or UK validation cohorts in the low-risk and moderate-risk groups., Conclusion: We derived a 4-variable prediction rule that can be used to stratify patients with early dcSSc into groups by risk of 2-year mortality, and we validated that prediction rule in US and UK cohorts., (Copyright © 2014 by the American College of Rheumatology.)

Objective: To assess the prevalence of systemic sclerosis (SSc) in the Lorraine region, France., Methods: Data from three sources - general practitioners and community and hospital specialists, medical records departments, and regional and national laboratories-and a capture-recapture method with log-linear models were used to estimate SSc prevalence in the region. Double recording was checked, and reported cases were validated after a review of medical records., Results: We identified 560 records of suspected SSc cases corresponding to 327 unique suspected SSc cases existing on June 30, 2006, in Lorraine. On the basis of the 193 validated cases (22 [11.4%] with diffuse disease, 136 [70.5%] with limited disease, 31 [16.1%] with limited involvement and 4 unknown), the observed overall crude prevalence of SSc was 105.4 cases per million adult inhabitants (95% confidence interval [CI]: 91.0; 121.4). With the capture-recapture method, the estimated number of SSc cases was 233 (95% CI: 217.3; 260.0), so an estimated 40 cases were not identified by the three sources. The estimated overall prevalence was 132.2 cases per million adult inhabitants (95% CI: 115.8; 154.0)., Conclusions: Our study provides the first estimate of SSc prevalence in the Lorraine region. The capture-recapture method allowed us to estimate an additional 21% of unobserved cases and is a good alternative to the community-based study design for estimating the prevalence of rare diseases., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Objectives: This paper aims to investigate the incidence of scleroderma spectrum disorders (SDS) in Slovenia., Methods: From 01.01.2007 to 31.12.2009 we prospectively examined all patients over 18 years of age suspected of suffering from SDS who were referred to our department, which is the only Rheumatology referral centre in the Ljubljana region serving a population of 518.921 Caucasians over 18. Patient work-up consisted of clinical assessment, laboratory and imaging studies, and functional tests. The working classification of SDS proposed by Maricq and Valter was used to classify patients as having CREST syndrome, digital scleroderma disease (SD), intermediate SD, diffuse SD, undifferentiated connective tissue disease with SD features, and SD sine scleroderma. Patients with certain features of SDS who did not fit any specific class were classified as having prescleroderma using LeRoy's classification of early systemic sclerosis., Results: We examined 100 patients. Forty-one new cases of SDS were diagnosed (37 females, 4 males), aged 58.9±15.1 years (24-86 years)., Conclusions: The overall age-adjusted annual incidence of SDS in Slovenia is 2.6 per 100.000 adults per year (95%CI=1.7-3.5).

Objectives: To determine the clinical characteristics of simultaneous occurrence of antitopoisomerase (ATA) and anticentromere (ACA) autoantibodies in systemic sclerosis (SSc)., Methods: Data of patients (n=4,687) fulfilling the ACR criteria for SSc and followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. Sera from patients with simultaneous ATA and ACA were reanalyzed centrally by indirect immunofluorescence, enzyme immunoassay, and immunoblot to confirm antibody status., Results: A total of 29 patients (0.6%) had been documented double-positive for both ATA and ACA in the EUSTAR database. Sera of 14 cases were available for central analysis, of which 8 were confirmed to unequivocally contain both antibodies. The double-positive patients were on average 52.4 years of age, 87.5% were female, and 62.5% had diffuse cutaneous (dc) SSc. Compared with matched ACA single-positive disease, cutaneous and visceral complications were more prevalent in double-positive cases, but this prevalence did not differ significantly in comparison to ATA single-positives., Conclusions: Coexistence of ATA and ACA can be found at low prevalence in SSc. The clinical features of double-positive patients are not clearly dissimilar to those of patients harbouring only ATA. The data do not support a direct involvement of these antibodies in the pathogenesis of established SSc, but may lack statistical power.

Systemic sclerosis is a chronic inflammatory multiorgan disease belonging to the group of collagen-vascular disorders. With a prevalence of 10/100,000 inhabitants it may be regarded a rather rare disease. Its etiology and pathogenesis have still not been elucidated in detail, especially with regard to the differential involvement of skin and the cause of the clinically heterogeneous disease courses. Various components of the vasculature, connective tissue as well as the immune system are involved in a yet unknown sequence and significance. Patients need to be cared for in an interdisciplinary fashion depending on the individual organ involvement. Apart from the skin, the heart, kidneys and lungs are mainly affected in addition to frequent gastrointestinal and musculoskeletal symptoms. Clinically two distinct subsets may be separated, acral (also termed limited) and diffuse scleroderma, which are characterized by anti-centromere and anti-Scl-70/topoisomerase-1 antibodies, respectively. Recent data demonstrate a poor prognosis even in limited disease when pulmonary arterial hypertension develops at an early stage. In diffuse disease sudden and rapid onset will result in a sclerosis of major internal organs and early death in many cases., (© The Author • Journal compilation © Blackwell Verlag GmbH, Berlin.)

Objective: To assess the prevalence of SSc in south-east Norway., Methods: The survey was conducted in south-east Norway with a denominator population of 2,707,012, 56% of the total Norwegian population. All SSc patients living in the study area between 1 January 1999 and 31 December 2009 were included. Patients were identified by five overlapping acquisition routes, including all the rheumatology departments, private rheumatologists and the dermatology department in the study area. Only cases meeting the 1980 ACR and/or the Medsger and LeRoy classification criteria were included. The patients were assigned to three clinical subsets: limited SSc, lcSSc or dcSSc., Results: At the end of the study period, a total of 269 patients fulfilled the ACR and/or the Medsger and LeRoy SSc criteria, giving a point prevalence of 9.9/100,000 (95% CI 8.8, 11.2). The estimated prevalences of lSSc, lcSSc and dcSSc were 1.3/100,000, 6.9/100,000 and 1.8/100,000 (95% CIs 0.9, 1.8; 5.8, 7.8; 1.4, 2.5), respectively. The mean age at onset was 47 years and the female:male ratio was 3.8:1. The prevalence estimates of SSc in the 10 different counties in south-east Norway varied between 5.2 and 14.4/100,000 (95% CIs 2.8, 8.8; 10.3, 19.6)., Conclusion: This study establishes baseline estimates of the occurrence and disease characteristics in a large, unselected group of Norwegian SSc patients. Our data suggest that the prevalence of SSc in Norway is comparable with other northern European countries, supporting the notion of a north-south gradient of SSc in Europe with the lowest prevalence in northern Europe.

Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease. Of the numerous organ manifestations, involvement of the upper and lower gastrointestinal tract (GIT) appears to be the most frequent with regard to the clinical symptoms. However, as the frequency and clinical relevance of GI involvement in patients with SSc are not known in detail, the German network of the systemic sclerosis (DNSS) has developed a detailed questionnaire to evaluate the extent and profile of gastrointestinal involvement in SSc patients. The multi-symptom questionnaire was used at baseline and after 1 year in registered patients of the DNSS. In addition, the results were compared with gastrointestinal disorders in patients with SSc and other rheumatic diseases, as well as with the medical history of the patients. In total, 90 patients were included in the study. The results of the study show that in reality, a much higher (nearly all) percentage of (98,9%) patients than expected suffer from GI-symptoms, regardless of the stage of their disease. Of these, meteorism (87,8%) was the most common followed by coughing/sore voice (77,8%), heartburn (daytime 68,9%, nighttime 53,3%), diarrhea (67,8%), stomach ache (68,9%) and nausea (61,1%). Although SSc patients were treated according to the respective recommendations, only limited improvements with regard to GI-symptoms could be achieved after 1 year of follow-up. In addition, the study revealed that the multi-symptom questionnaire is a useful tool to contribute to identify the gastrointestinal sequelae in systemic sclerosis.

Anti-CCP (cyclic citrullinated peptide) is considered the most useful laboratory tool in the diagnosis of rheumatoid arthritis (RA). Some authors have also found this autoantibody in patients with scleroderma (SSc). The study aimed to investigate the prevalence of anti-CCP antibodies in SSc patients from Southern Brazil and their association with clinical and serological profile of the disease. We studied 76 patients with SSc and 100 healthy volunteers for presence of anti-CCP. SSc patients charts were reviewed for clinical and laboratory data. In the SSc group, the diffuse form was present in 20.5%; 62.8% had the limited form; 14.1% had overlap with systemic lupus or polymyositis and 2.5% had SSc sine scleroderma. Anti-CCP was found in nine of 78 (11.5%) SSc patients and in one of 100 healthy volunteers (p = 0.0054). No relationship was found with arthritis, skin Rodnan m score, esophageal dysmotility, myocarditis, pulmonary hypertension and lung fibrosis. Positive association was observed with arthralgias (p = 0.02). Also, no relationship was noted with the presence of anti-centromere antibodies, anti-Scl-70, anti-RNP or rheumatoid factor. Anti-CCP are more common in SSc patients than in controls. Arthralgias but not arthritis or rheumatoid factor are more frequent in anti-CCP positive patients.

Skin tightness is a major clinical manifestation of systemic sclerosis (SSc). Importantly for both clinicians and patients, spontaneous regression of the fibrosis process has been documented. The purpose of this study is to identify the incidence and related clinical characteristics of spontaneous regression among Thai SSc patients. A historical cohort with 4 years of follow-up was performed among SSc patients over 15 years of age diagnosed with SSc between January 1, 2005 and December 31, 2006 in Khon Kaen, Thailand. The start date was the date of the first symptom and the end date was the date of the skin score ≤2. To estimate the respective probability of regression and to assess the associated factors, the Kaplan-Meier method and Cox regression analysis was used. One hundred seventeen cases of SSc were included with a female to male ratio of 1.5:1. Thirteen patients (11.1%) experienced regression. The incidence rate of spontaneous skin regression was 0.31 per 100 person-months and the average duration of SSc at the time of regression was 35.9±15.6 months (range, 15.7-60 months). The factors that negatively correlated with regression were (a) diffuse cutaneous type, (b) Raynaud's phenomenon, (c) esophageal dysmotility, and (d) colchicine treatment at onset with a respective hazard ratio (HR) of 0.19, 0.19, 0.26, and 0.20. By contrast, the factor that positively correlated with regression was active alveolitis with cyclophosphamide therapy at onset with an HR of 4.23 (95% CI, 1.23-14.10). After regression analysis, only Raynaud's phenomenon at onset and diffuse cutaneous type had a significantly negative correlation to regression. A spontaneous regression of the skin fibrosis process was not uncommon among Thai SSc patients. The factors suggesting a poor predictor for cutaneous manifestation were Raynaud's phenomenon, diffuse cutaneous type while early cyclophosphamide therapy might be related to a better skin outcome.

CREST syndrome is part of the heterogeneous scleroderma group of autoimmune diseases that cause thickening, hardening and tightening of the connective tissue in different parts of the body, and it may lead to complex disorders. CREST syndrome is characterized by the coexistence of calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactily and telangectasia. A 72-year-old caucasian woman is referred to the S. Gerardo Hospital of Monza, with a chief complaint of oral pain and difficulties in deglutition and eating, associated with denture instability and difficulties to fit it. She had been previously diagnosed with Raynaud's phenomenon, and afterwards with CREST syndrome. Extra-oral examination underlined taut, thickened and rigid skin, pallid-red irregular maculae all over the face, telangiectasias and acrocyanosis. Intra-oral examination showed no alteration of the mucosa, but we can observe tongue rigidity and some speckled red alternating with white spots on the hard palate and in the vestibule. We undermitted the patient the dental treatment of Sjogren's syndrome. The management of the Sjogren's syndrome is symptomatic and empirical, and involves the use of saliva secretion stimulators, salivary substitutes and coadjuvants. Dental treatment and prophylaxis are important to prevent the consequences of xerostomia, such as rampant caries, based on the administration of topical fluoride in toothpastes and rinses, and supplemented by fluoride gels and varnishes. Instruction and reinforcement of oral hygiene, along with frequent dental assessment and management by the dentist are essential measures to preserve the oral health of those affected with CREST syndrome in progression to SS, complicated with Sjogren's syndrome.

The pathophysiological relationship between scleroderma and malignancy remains poorly understood. Although some previous studies have demonstrated an increased malignancy risk in patients with scleroderma, others have been inconclusive. We aimed to determine if patients with scleroderma had an increased risk of malignancy compared to an age- and sex-matched local South West England population, and if there were any important differences between scleroderma patients with and without malignancy. Methods of this study are as follows. Notes were obtained on all local scleroderma patients (n = 68) locally, and those diagnosed with malignancy verified by contacting each patient's general practitioner. Expected malignancy figures were obtained from age- and sex-stratified regional prevalence data provided by the South West Cancer Intelligence Service registry. Among the patients, 22.1% with scleroderma were identified with concurrent malignancy. Affected sites were of the breast (n = 5), haematological system (n = 5), skin (n = 4), and unknown primary (n = 1). Overall, malignancy risk was found to be increased in scleroderma (RR = 3.15, 95% CI 1.77-5.20, p = 0.01). In particular, this risk was the highest for haematological malignancies (RR = 18.5, 95% CI 6-43, p = 0.03), especially for non-Hodgkin's lymphoma (RR = 25.8, 95% CI 5-75, p = 0.10). The majority of patients (86.7%) developed malignancy after the onset of scleroderma (mean = 6.9 years). Age of >70 and patients with limited scleroderma were significant risk factors for a patient with scleroderma to have a concurrent malignancy; however, no increased risk was found in patients with any particular pattern of organ involvement, cytotoxic usage or serology. To conclude, in this small patient cohort, we have found that scleroderma is associated with an increased risk of malignancy. This risk is statistically significant in patients with limited scleroderma. Patients who are elderly and those with limited disease should be closely scrutinized at follow-up appointments.

Background: The diffuse sclerosing variant of papillary thyroid carcinoma (DSPC) is a relatively rare variant of papillary thyroid cancer. Large studies of patients with DSPC have been infrequently performed, and controversy still exists concerning some DSPC features and outcomes. The aim of the present study was to retrospectively evaluate the clinicopathologic features and outcomes in a series of 34 consecutive patients with DSPC and to compare them with a larger group of 245 consecutive patients with the classic variant of papillary thyroid carcinoma (cPTC) that were evaluated in the same period., Patients and Methods: Clinical and histological features (sex, age, tumor size,multifocality, bilaterality, extra thyroid extension, and local and distant metastases) were recorded in all patients, as well as any persistent or recurrent disease and the patients' disease status at last observation. Patients with cPTC were classified as either low (122) or high risk (123). DSPC and high-risk patients were all treated with the same protocol, including ¹³¹I treatment. All patients were included in a Cox regression model analysis to investigate the effect of each variable on the hazard ratio., Results: As expected, multifocality, bilaterality, and extra thyroid extension were more frequently noted at presentation, and the pT1 category of TNM classification was less frequently noted in DSPC and high-risk patients with cPTC compared with low-risk patients with cPTC. No significant difference was found between patients with DSPC and those with high-risk cPTC, except that extra thyroid extension was found more frequently in the patients with DSPC. Using multivariate analysis, diffuse sclerosing variant was an independent variable for predicting a high risk of persistent and recurrent disease during initial follow-up. However, at a later time, and after further treatment, the disease status was not different between patients with DSPC and those with high-risk cPTC, and only the presence of distant metastases affected the final outcome., Conclusions: DSPC is a thyroid papillary carcinoma variant characterized by high aggressiveness. In patients with DSPC, the outcome is worse than in patients with low-risk cPTC; and, at presentation, characteristics are somewhat worse than for patients with high-risk cPTC.At medium term, the outcome is similar to that observed in patients with high-risk cPTC, provided aggressive treatment is used (additional surgical intervention, when required, and/or ¹³¹I radiotherapy).

Objective: To examine the predictive role of HLA genetic markers in scleroderma renal crisis (SRC), beyond the known clinical correlates, in a large population of patients with systemic sclerosis (SSc)., Methods: SSc patients from the Scleroderma Family Registry and DNA Repository, the Genetics versus Environment in Scleroderma Outcomes Study, and the rheumatology division registry at the University of Texas Health Science Center at Houston were included in the study. Relevant clinical data were obtained by chart review, and autoantibodies were detected utilizing commercially available kits. HLA class II genotyping was performed on extracted and purified genomic DNA., Results: Overall, 1,519 SSc patients were included in the study, of whom 90 (6%) had developed SRC. Among the 90 patients with SRC, the diffuse cutaneous disease subtype was found in 76%, antitopoisomerase antibodies (antitopo) in 9%, anticentromere antibodies (ACAs) in 2%, and anti-RNA polymerase III (anti-RNAP III) in 50% of patients. In multivariate analyses of clinical and demographic parameters, diffuse disease type and anti-RNAP III were strong risk factors for the presence of SRC, whereas ACAs and antitopo were protective. In the final multivariate analysis, which included HLA alleles, HLA-DRB1*0407 (odds ratio [OR] 3.21, 95% confidence interval [95% CI] 1.27-8.08; P = 0.013) and DRB1*1304 (OR 4.51, 95% CI 1.30-15.65; P = 0.018) were identified as independent risk factors for SRC. Only 3 clinical characteristics, diffuse disease type, anti-RNAP III, and ACAs, remained significantly associated with SRC in the final model., Conclusion: The results of this study suggest that DRB1*0407 and *1304 are independent risk factors, beyond the known clinical correlates, for the development of SRC., (Copyright © 2011 by the American College of Rheumatology.)

Systemic sclerosis (SSc) is a multisystem auto-immune disease. The two main subtypes of SSc (limited and diffuse) typically have differing courses and prognoses. New classification criteria have been proposed to identify SSc in the earliest stages, before skin involvement. Over the past three decades, there has been an apparent increase in the incidence of SSc to approximately 20 per million, possibly due to improved diagnosis. The most extensively studied environmental associations of SSc are organic solvents and silica but no single risk factor has emerged. Recent genetic studies have identified new susceptibility factors including human leucocyte antigen (HLA) haplotypes and polymorphisms in immune regulatory genes. Despite earlier disease recognition and effective treatment for some of its complications, SSc still carries a high mortality, particularly due to cardiorespiratory complications. Although some predictors of organ involvement and outcomes have been identified, novel biomarkers are greatly needed. Due to low disease prevalence, large multicentre research collaborations are required., (2010. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate sera titers for antibodies anti-cyclic citrullinated peptide and their correlation against sera levels of anti-topoisomerase I and anti-centromere antibodies in Mexican patients with systemic sclerosis., Patients and Methods: Consecutive outpatients with systemic sclerosis who attending to rheumatology clinic at a second level hospital facility. The antibodies anti-cyclic citrullinated peptide, anti-topoisomerase I and anti-centromere were determined by enzymatic immunoassay (ELISA)., Statistical Analysis: Spearman for correlation between numerical variables with nonparametric distribution. Fisher exact test or chi2 to compare proportions and Student t test for dimensional variables., Results: Thirty female patients were included; aged 53 +/- 13, the disease duration at the time of the study was 10 +/- 9. Twenty-three patients (77%) exhibited diffuse disease. Anti-centromere, anti-topoisomerase I, and anti-cyclic citrullinated peptide were detected in nine, nine and three patients respectively. The correlation analysis showed the independence of autoantibodies anti-centromere and anti-topoisomerase I with respect to the levels of anti-cyclic citrullinated peptide., Conclusions: This study confirms the low frequency of anti-cyclic citrullinated peptide antibodies in patients with systemic sclerosis. A lack of correlation between autoantibodies considered as "mutually excluded" anti-topoisomerase I and anti-centromere, indicating that the analysis of the relevance for anti-cyclic citrullinated peptide in systemic sclerosis must include other clinical and serological variables.

The pathogenesis of scleroderma encompasses vascular, immunological, and fibrotic processes, which contribute to clinical manifestations. We investigated the prevalence of anti-annexin V IgG and IgM antibodies in sera of scleroderma patients and their relation to the presence of other antibodies and development of disease morbidity. Sera of 40 scleroderma patients and 15 healthy controls were examined for IgG and IgM anti-annexin V antibodies by ELISA and anticentromere antibodies by indirect immunofluorescence. Serum level of anti-annexin V IgG antibodies in scleroderma patients was significantly higher than that of the control (P < 0.001) and correlated significantly with the presence of digital ischemia (P = 0.023) and pulmonary fibrosis (P = 0.02). IgM isotype was comparable between patients and controls (P = 0.317). Anticentromere antibodies are more prevalent in the limited cutaneous subtype (P = 0.017). In conclusion, measurement of serum anti-annexin V IgG antibodies in scleroderma patients may be important for early diagnosis of vascular and pulmonary complications.

Background: Stiff skin syndrome is a sclerodermalike disorder that presents in infancy or early childhood with rock-hard skin, limited joint mobility, and mild hypertrichosis in the absence of visceral or muscle involvement, immunologic abnormalities, or vascular hyperreactivity., Observations: We describe 6 children who fit criteria for stiff skin syndrome. A review of the clinical range of this disorder and discussion of the differential diagnosis is presented. The age at onset in our cases ranged from infancy to 6 years of age. Stony-hard skin was noted mostly on the thighs, buttocks, and lower back with shoulder and arm involvement in 2 cases. There was associated hypertrichosis in 3 of 6 cases. Extracutaneous manifestations consisted primarily of joint restriction, and several patients had resulting postural and thoracic wall irregularities. Histopathologically, our cases showed areas of fascial sclerosis or showed increased fibroblast cellularity with thickened, sclerotic, horizontally oriented collagen bundles in the deep reticular dermis and/or subcutaneous septa without associated inflammation., Conclusions: Stiff skin syndrome is characterized by an early, insidious onset of stony-hard skin, often with associated contracturelike joint restriction, hypertrichosis, and postural and thoracic wall abnormalities. Supportive histopathologic findings consisting of either fascial sclerosis or increased fibroblast cellularity with sclerotic collagen bundles in the deep reticular dermis and/or subcutaneous septa may help to confirm this diagnosis.

Objective: Systemic sclerosis (SSc) is a rare, heterogeneous disease, which affects different organs and therefore requires interdisciplinary diagnostic and therapeutic management. To improve the detection and follow-up of patients presenting with different disease manifestations, an interdisciplinary registry was founded with contributions from different subspecialties involved in the care of patients with SSc., Methods: A questionnaire was developed to collect a core set of clinical data to determine the current disease status. Patients were grouped into five descriptive disease subsets, i.e. lcSSc, dcSSc, SSc sine scleroderma, overlap-syndrome and UCTD with scleroderma features., Results: Of the 1483 patients, 45.5% of patients had lcSSc and 32.7% dcSSc. Overlap syndrome was diagnosed in 10.9% of patients, while 8.8% had an undifferentiated form. SSc sine scleroderma was present in 1.5% of patients. Organ involvement was markedly different between subsets; pulmonary fibrosis for instance was significantly more frequent in dcSSc (56.1%) than in overlap syndrome (30.6%) or lcSSc (20.8%). Pulmonary hypertension was more common in dcSSc (18.5%) compared with lcSSc (14.9%), overlap syndrome (8.2%) and undifferentiated disease (4.1%). Musculoskeletal involvement was typical for overlap syndromes (67.6%). A family history of rheumatic disease was reported in 17.2% of patients and was associated with early disease onset (P < 0.005)., Conclusion: In this nationwide register, a descriptive classification of patients with disease manifestations characteristic of SSc in five groups allows to include a broader spectrum of patients with features of SSc.

Objective: To determine the prevalence and characteristics of moderate to severe pulmonary hypertension (PH) in patients with systemic sclerosis (SSc) with and without interstitial lung disease (ILD)., Methods: We retrospectively studied clinical and functional characteristics of 197 consecutive patients with SSc who had undergone a screening echocardiography to detect PH., Results: Moderate to severe PH was suspected in 36 patients (18.3%) and confirmed in 32 who underwent right heart catheterization. The prevalence of PH did not differ between patients with limited and patients with diffuse cutaneous SSc. PH was detected in 12/67 (17.9%) patients without ILD vs 24/110 (21.8%) patients with ILD (p not significant). In patients with ILD, a lower PaO2 appeared as the unique independent factor significantly associated with PH, regardless of the extent of fibrosis. In 3 patients out of 9 (33.3%) with ILD and significantly restrictive disease, PH was out of proportion to the degree of fibrosis. In patients with no ILD, a higher grade of dyspnea appeared as the unique independent factor associated with PH. In patients with no ILD, altered DLCO was the sole indicator of the pulmonary function tests associated with PH (best cutoff value 72%). DLCO correlated with systolic pulmonary arterial pressure only in patients with no ILD., Conclusion: Prevalence of moderate to severe PH was similar in SSc patients with and those without ILD. In patients with ILD, a lower PaO2 was the unique independent indicator associated with PH. In some patients with severe ILD, PH was out of proportion to the degree of fibrosis. A linear correlation between DLCO and systolic pulmonary arterial pressure was observed only in patients without ILD. All these indicators should assist identification of patients with or without ILD requiring diagnostic procedures for PH before annual screening.

This study aims to characterize the clinical features of a cohort of patients diagnosed with systemic sclerosis (SSc) after the age of 75 and compare them to a group diagnosed at a younger age. We record the review of 769 patients diagnosed with SSc over the past 16 years. Utilizing a nested case-control model, we compare demographics, disease severity, morbidity, and mortality data of all patients diagnosed after the age of 75 to sex- and disease-type-matched, randomly selected group of patients diagnosed with SSc before the age of 60. Twelve patients were diagnosed with SSc after the age of 75, seven with the diffuse, and five with the limited form. It took longer to diagnose SSc in the older patients, and comparison of disease severity revealed a worse pulmonary picture and a more frequent development of malignancy in the older patients as compared with the younger ones. During a mean follow-up of 36.2 months, our cohort of patients did not have worsening in their disease severity, though 6 months after the last follow-up, six patients died. We conclude that a diagnosis of SSc at an older age appears to be a poor prognostic indicator related to both disease severity and comorbidities. A higher clinical suspicion will lead to an earlier diagnosis and a potential decrease in morbidity and mortality.

The aim of this study was to determine the incidence, prevalence, survival and selective demographic characteristics of scleroderma occurring in South Australia over the 10-year period 1993-2002. Analysis of the database of the South Australian Scleroderma Register: a population-based register established in 1993. Patients with scleroderma resident in South Australia (n = 353 at 2002) were ascertained from multiple sources and clinical and demographic data were obtained from mailed questionnaire and from review of computerized hospital databases, case notes or referring letters. Time-space cluster analysis was carried out according to the Knox method. Control data were obtained from the Australian Bureau of Statistics census. The mean prevalence was 21.4 per 10(5) (95% confidence interval 20.2-22.6) and the mean cumulative incidence of 1.5 per 10(5) (95% confidence interval 1.32-1.73) with no significant change in incidence over the study period (P = 0.13). Cumulative survival improved over the study period, with patients with diffuse disease having significantly reduced survival (as compared with limited disease, P < 0.001). The proportion with diffuse disease ( approximately 22%) remained steady. There was a small but significant predisposition in patients with a continental European birthplace (P < 0.001). A family history of scleroderma was noted in 1.6% with lambda1 (familial risk) of 14.3 (95% confidence interval 5.9-34.5). However, a family history of systemic autoimmunity (especially rheumatoid arthritis) was more common (6%). No socioeconomic stratification, temporal clustering nor spatio-temporal clustering was observed either at time of initial symptom or at 10 years before disease onset. Scleroderma occurs relatively infrequently in South Australia with no significant change in incidence observed over the 10-year study period. However, cumulative survival has improved. Identified risk factors include family history of scleroderma (risk approximately 14-fold), female sex (risk approximately 5-fold) and European birthplace (risk approximately 2.5-fold); however, the majority of the disease variance appears unexplained. A stochastic explanation based on genetic instability is favoured to explain this paradox.

To use Doppler tissue imaging to evaluate heart function and to predict rehospitalization rate in progressive systemic sclerosis, we studied 40 patients (limited in 24 patients, diffuse in 16 patients) with chest roentgenography, pulmonary function test, routine echocardiography, and myocardial Doppler tissue. Another 45 volunteers without any sign of heart failure served as the control group. Significant difference of echocardiographic parameters was found in peak transmitral early diastolic velocity, right ventricular (RV) ejection fraction (EF) (RVEF), pulmonary artery systolic pressure, and Doppler tissue parameters of the RV and septum (peak transmitral early diastolic velocity, P = .012; RVEF, P < .0001; pulmonary artery systolic pressure, P < .0001). The parameters derived by pulsed wave Doppler tissue decreased in RV, including peak systolic myocardial velocity (Sm), early diastolic velocity, late diastolic velocity, and myocardial performance index. RVEF and left ventricular EF were estimated by Simpson's method. RV-Sm could be used to identify RV failure. Receiver operating characteristic area under the curve for RV-Sm was 0.935. RV-Sm less than 11 cm/s indicted RVEF less than 40% with sensitivity of 87% and specificity of 86%. Contrary to expectation, pulmonary artery systolic pressure was not so well correlated with RV function. The frequency of admission was reverse correlated with decrement of RV-Sm in patients with RV-Sm less than 12 cm/s. We conclude that in progressive systemic sclerosis, RV systolic dysfunction is common and appears to be a result of pulmonary hypertension, disturbance of myocardial microcirculation, and myocardial fibrosis. Pulmonary hypertension was not well correlated with RV dysfunction; it suggested pulmonary hypertension was not the only cause of RV failure. Primary right heart involvement was the other possible cause. By myocardial Doppler tissue imaging, we can predict the frequency of hospitalization; it suggests simultaneous involvement of heart, skin, lung, and other organs. RV-Sm more than 12 cm/s predicted a decreased likelihood of readmission to the hospital.

Objective: To determine the frequency and severity of kidney abnormalities in patients with diffuse scleroderma., Methods: All patients with diffuse scleroderma seen at the University of Pittsburgh between 1972 and 1993 were included in the study. Kidney function tests were routinely obtained as part of the Pittsburgh Scleroderma Outcome Study. Additional kidney tests were obtained as part of the 1992 biannual outcome assessment. Patients who had kidney abnormalities including a serum creatinine > 1.2 mg/dl or proteinuria prior to 1993 were identified. The clinical setting and longterm outcome of kidney disease were evaluated., Results: Renal crisis occurred in 129/675 (19.5%) patients. Kidney function abnormalities or proteinuria were present in 173 (26%); 48% had no abnormalities. Most patients had other explanations for the abnormality. Only 12 (2%) of the 675 patients with diffuse scleroderma had no explanation for the elevated creatinine level. Most patients with proteinuria had toxicity from D-penicillamine. No explanations for proteinuria were found in 16 (2%) of this cohort. Thus, a total of only 28 (4%) of these 675 patients had an unknown cause for their kidney dysfunction or proteinuria. None of these patients, who were followed for a mean of 10 years after onset of scleroderma, have developed chronic renal insufficiency that progressed to dialysis., Conclusion: Patients with diffuse scleroderma without renal crisis rarely have significant increases in serum creatinine or proteinuria that cannot be explained by other etiologies. These patients with scleroderma should be carefully evaluated for non-scleroderma causes of kidney disease.

Objective: To assess the prevalence of systemic sclerosis (SSc) in a French multi-ethnic population and to examine ethnic differences., Methods: This survey was conducted in Seine-Saint-Denis County, a suburb of Paris, home to 1,094,412 adults (>/=15 yr), among whom 26% are of non-European background with mainly northern and sub-Saharan African, Asian and Caribbean ancestries. The study period comprised the entire calendar year 2001. Patients were ascertained through four sources: public and private hospitals, general practitioners and community specialists, the French SSc patient support group, and the National Public Health Insurance System database. Only cases meeting either the 1980 ACR and/or LeRoy and Medsger's classification criteria were included and assigned to three clinical subsets: limited (normal skin) (l), limited cutaneous (lc) or diffuse cutaneous (dc) SSc. Capture-recapture (CR) analyses using log-linear modelling were performed to correct for incomplete case finding., Results: We retained a total of 119 patients with SSc, including 15 extrapolated from inaccessible files. CR analysis estimated that 54.2 additional cases were missed by all the sources. The overall SSc prevalence (per million adults) was 158.3 (95% confidence interval, 129-187); those of lSSc, lcSSc and dcSSc were, respectively, 32.3 (16-48), 83.1 (66-101) and 42.9 (25-60); and respective values for Europeans and non-Europeans were 140.2 (112-170) and 210.8 (128-293)., Conclusion: Regarding the heterogeneity of previously published estimates, this population-based survey using CR analysis might contribute to obtaining a better appraisal of SSc prevalence. Despite overlapping confidence intervals, the higher prevalence observed for non-Europeans could support potential influences of ethnic origin on the pathogenesis of SSc.