dcSSc Subtype Research Articles

Metabolic fingerprinting of systemic sclerosis: a systematic review.

Introduction: Systemic sclerosis (SSc) is a chronic autoimmune disease, marked by an unpredictable course, high morbidity, and increased mortality risk that occurs especially in the diffuse and rapidly progressive forms of the disease, characterized by fibrosis of the skin and internal organs and endothelial dysfunction. Recent studies suggest that the identification of altered metabolic pathways may play a key role in understanding the pathophysiology of the disease. Therefore, metabolomics might be pivotal in a better understanding of these pathogenic mechanisms. Methods: Through a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Guidelines (PRISMA), searches were done in the PubMed, EMBASE, Web of Science, and Scopus databases from 2000 to September 2022. Three researchers independently reviewed the literature and extracted the data based on predefined inclusion and exclusion criteria. Results: Of the screened studies, 26 fulfilled the inclusion criteria. A total of 151 metabolites were differentially distributed between SSc patients and healthy controls (HC). The main deregulated metabolites were those derived from amino acids, specifically homocysteine (Hcy), proline, alpha-N-phenylacetyl-L-glutamine, glutamine, asymmetric dimethylarginine (ADMA), citrulline and ornithine, kynurenine (Kyn), and tryptophan (Trp), as well as acylcarnitines associated with long-chain fatty acids and tricarboxylic acids such as citrate and succinate. Additionally, differences in metabolic profiling between SSc subtypes were identified. The diffuse cutaneous systemic sclerosis (dcSSc) subtype showed upregulated amino acid-related pathways involved in fibrosis, endothelial dysfunction, and gut dysbiosis. Lastly, potential biomarkers were evaluated for the diagnosis of SSc, the identification of the dcSSc subtype, pulmonary arterial hypertension, and interstitial lung disease. These potential biomarkers are within amino acids, nucleotides, carboxylic acids, and carbohydrate metabolism. Discussion: The altered metabolite mechanisms identified in this study mostly point to perturbations in amino acid-related pathways, fatty acid beta-oxidation, and in the tricarboxylic acid cycle, possibly associated with inflammation, vascular damage, fibrosis, and gut dysbiosis. Further studies in targeted metabolomics are required to evaluate potential biomarkers for diagnosis, prognosis, and treatment response.

Native T1 mapping in early diffuse and limited systemic sclerosis, and its association with diastolic function

BackgroundSystemic sclerosis (SSc) is divided into diffuse and limited cutaneous SSc (dcSSc and lcSSc). The dcSSc subtype has more severe internal organ damage. This study aimed to assess whether cardiovascular magnetic resonance (CMR) parametric mapping could detect early cardiac involvement and evaluate differences between these two subtypes. MethodsEighty SSc patients (37 dcSSc and 43 lcSSc) underwent CMR at 3.0 T (Philips Healthcare, Best, The Netherlands) in our hospital between July 2018 and July 2021. We analyzed myocardial damage by CMR parametric mapping and compared it with clinical data. ResultsThe median duration of the disease was 10.2 months. The left ventricular ejection fraction was preserved in both groups. DcSSc had significantly higher native T1 (1333.4 ± 71.2 ms vs. 1295.0 ± 42.7 ms, p = 0.006) and extracellular volume fraction (32.6 ± 4.1 % vs. 30.3 ± 4.0 %, p = 0.018) in the mid-ventricular septum as compared to lcSSc, although there were no differences in T2 values. Native T1 values were positively correlated with the E/e’ ratio and left atrial volume indices evaluated by transthoracic echocardiography in overall SSc and dcSSc, but not in lcSSc. Logistic regression analysis revealed that native T1 was an independent predictor of left ventricular diastolic dysfunction in SSc patients (odds ratio, 1.194; 95 % confidence interval, 1.021–1.396; p = 0.026). Native T1 was higher in SSc patients with progressive skin lesions. Additionally, there were positive correlations between brain natriuretic peptide, New York Heart Association functional classification, and native T1. ConclusionsCMR parametric mapping is a useful tool for detecting myocardial changes. Native T1 was the most sensitive parameter for identifying diffuse myocardial changes in the early stages of SSc and was associated with left ventricular diastolic function. DcSSc had more severe myocardial involvement than lcSSc; therefore, the use of CMR parametric mapping may aid in its prediction.

Clinical assessment of patients with systemic sclerosis: is there a place for thermography?

Recurrent changes of temperature and persistence of cooling along fingers at the room temperature make hands the most frequent region of interest for thermography in systemic sclerosis (SSc). The aim of this study was to evaluate dependance of temperature in hands on a subtype of the disease, immune profile of antinuclear antibodies (ANA), and lung involvement. There were 29 patients with limited cutaneous involvement (lcSSc) and 10 patients with diffuse cutaneous disease (dcSSc) enrolled for the study. To compare measurements to normal values, there were enrolled 29 healthy volunteers (control group). All participants were submitted to thermography with handheld camera FLIR One Pro for iOS, attached to mobile phone iPhone 11, at the fixed temperature of 21°C. Measurements included average temperature (Tavg) over nailfolds in thumbs and fingers II-V, as well as the difference in average temperatures (TΔ) between metacarpus of the hand and its thumb and fingers II-V. Both thumbs and fingers II-V remained cooler in subjects with dcSSc compared to those with lcSSc. This implicated a significantly greater TΔ along thumbs and fingers II-V in dcSSc group. Although Tavg at nailfolds in SSc patients was not lower than in healthy controls, TΔ remained significantly more pronounced in both lcSSc and dcSSc subjects. A positivity to ACA in lcSSc group was found to be associated with significantly lower Tavg and more pronounced TΔ in fingers II-V than the presence of anti-Scl70 antibodies. Temperature measurements remained statistically independent on a presence of ILD in lcSSc group, but both thumbs and fingers II-V in dcSSc group were warmer in case of lung involvement. The study showed the dcSSc subtype, the positivity of ACA in lcSSc, but not lung involvement were associated with poorer thermal control in the hands of SSc patients. A comparison to healthy controls highlighted the weakness of temperature measurements at nailfolds (Tavg) but increased the value of TΔ in thermography of hands.

Cardiac magnetic resonance parametric mapping can detect early cardiac involvement of patients with systemic sclerosis

Abstract Background Systemic sclerosis (SSc) is divided into two subtypes, diffuse and limited cutaneous SSc (dcSSc and lcSSc). The dcSSc subtype has more severe internal organ fibrosis than lcSSc. It is unclear whether cardiovascular magnetic resonance (CMR) parametric mapping can detect early cardiac involvement in these two subtypes. Purpose To detect cardiac involvement and evaluate differences between the two subtypes, we examined CMR parametric mapping. Methods 57 consecutive SSc patients (27 dcSSc and 30 lcSSc) who visited our hospital from July 2018 to February 2021 and underwent CMR at 3.0T (Philips) were included. We analyzed myocardial damage using CMR parametric mapping and compared it with clinical data. Results Mean disease durations of dcSSc and lcSSc were 4.0±6.5 years and 4.4±8.3 years, respectively. Although there were no significant differences in LVEF (56.8±8.8 vs 59.6±7.2), the left and right atrial volume index were significantly larger in dcSSc compared with lcSSc (all p<0.05). Focal fibrosis as evaluated by late gadolinium enhancement was found in 9 SSc patients (15.7%) and 4 patients had pulmonary hypertension. DcSSc patients had significantly higher mid-ventricular native T1 (1350.8±73.2 vs 1312.9±52.1, p=0.029) and postcontrast T1 values (640.4±59.4 vs 604.6±42.5, p=0.015) as compared to lcSSc, although there were no significant differences in ECV and T2 values. Native T1 values in mid-ventricular septum were positively correlated with E/e' ratio of echocardiography in overall SSc patients and dcSSc patients but not in lcSSc patients (r=0.320, p=0.021; r=0.505, p=0.010; r=0.195, p=0.329). Native T1 values in mid-ventricular septum were also positively correlated with plasma levels of brain natriuretic peptide (BNP) in overall SSc patients and dcSSc patients but not in lcSSc patients (r=0.353, p=0.008; r=0.484, p=0.011; r=0.113, p=0.559).The multiple regression analysis considering age and sex revealed that mid-ventricular septum native T1 was the independent predictor of E/e' in SSc patients (β=0.306, p=0.026), and dcSSc patients (β=0.553, p=0.007) but not in lcSSc patients (β=−0.282, p=0.105). The ROC curve for predicting E/e'≥14, cut-off value of native T1 in mid-ventricular septum was ≥1348.5msec (AUC 0.762; 95% CI 0.571–0.953; sensitivity 80.0%; specificity 68.1%). BNP was significantly higher in patients with native T1≥1348.5 msec compared with native T1<1348.5 (102.8±112.8 vs 45.7±55.7; p=0.014). The interobserver variability of CMR parametric mapping values was excellent in this study. Conclusion DcSSc patients showed higher native T1 and larger left and right atrial volume index of CMR than lcSSc patients, suggesting that DcSSc patients had more severe myocardial involvement and left ventricular diastolic dysfunction than lcSSc patients. Early detection of the high native T1 may predict the occurrence of cardiovascular events in the future. Funding Acknowledgement Type of funding sources: None. Correlation between native T1 and BNPCorrelation between native T1 and E/e'

P155 Co-existence of scleroderma hallmark autoantibodies associates with distinct clinical phenotype

Abstract Background Systemic sclerosis (SSc) is typically manifests with SSc-specific antibodies (SSc-Abs): anti-topoisomerase I (ATA), anti-centromere (ACA), anti-RNA polymerase III (ARA), anti-U3RNP (u3RNP), anti-U1RNP (U1RNP), anti-PmScl (PmScl), anti-Ku (Ku) and anti-Th/T0 (Th/T0), each being characterised by distinct clinical features and prognosis. The presence of > 1 SSc-Abs is rare with minimum data about these patients’ clinical phenotype in SSc Methods The autoantibody profiles of 2,799 SSc patients from February 2001 to June 2017 were retrospectively reviewed. Patients with >1 SSc-Abs were identified. Clinical features were collected and compared to historical cohorts of SSc patients with single SSc-Ab positivity. Patients were excluded if treated prior to their immunology test with rituximab, iv immunoglobulins or stem cell transplantation. Statistical analysis was performed using Fisher exact test. Results 72 patients (2.6%) with >1 SSc-Ab were identified. Full clinical data were available for 63 patients. 60 patients (2.1%) had double Ab positivity and 3 patients had triple Ab positivity (0.1%). 13 Ab combinations were present. U1RNP and ATA was the most frequent combination (35%), these patients were significantly younger(51.38 years) than both U1RNP (58.64 years,p=0.050) and ATA (62.03 years,p=0.002) patients and more commonly of diffuse subset (dcSSc)(p = 0.001 and p = 0.041 respectively). Compared to ATA patients overlap features were more frequent (43% vs 15%, p = 0.004) including inflammatory arthritis (p = 0.025) and myositis (p = 0.013) (Table 1). U1RNP and ACA had a significantly higher prevalence of pulmonary arterial hypertension compared to U1RNP (p = 0.039) and ACA (p = 0.022) patients, and compared to ACA patients they were younger (57.88 vs 68.75,p=0.015) with a higher frequency of myositis (p = 0.001). U1RNP and ARA patients were more frequently dcSSc subtype compared to U1RNP patients (75% vs 21%, p = 0.040). U1RNP and PmScl patients had a higher prevalence of myositis compared to U1RNP patients (p = 0.006). ATA and ACA patients behaved similarly to ATA patients with a significantly higher prevalence of lung fibrosis (p = 0.006) and myositis (p = 0.041) compared to ACA. ACA and PmScl (7%) had higher prevalence of myositis compared to ACA patients (p = 0.04). Conclusion Coexistence of hallmark autoantibodies is exceedingly rare in SSc patients. When combined, both SSc-Abs have the potential to synergistically interact and modify the clinical phenotype. Disclosures C. Campochiaro None. K.E.N. Clark None. L. Host None. A. Sari None. C.P. Denton None. V.H. Ong None.

Association of Musculoskeletal and Radiological Features with Clinical and Serological Findings in Systemic Sclerosis: A Single-Centre Registry Study.

Aim:Systemic sclerosis (SSc) is a chronic connective tissue disease with the clinical hallmark of skin thickening and tethering. Correlation of musculoskeletal features with other parameters should be considered in SSc patients.Methods:We reviewed the records of all patients who had more than one visit and standard anteroposterior radiography of hand. We used univariate analysis, and factors with p<0.05 were included in logistic regression to find out dependent factors.Results:Overall, 180 SSc patients were enrolled in our study, 161 (89.4%) of whom were women. Median age (IQR) was 47.0 years (16), and 52% had diffuse subtype of the disease. In multivariate analysis, tendon friction rubs (TFRs) was associated with the presence of calcinosis, muscle tenderness, and flexion contracture (FC) on physical examination (p<0.05). Arthritis showed no differences in the two subtypes of the disease (p=0.98), and in multivariate analysis, there were no correlations between radiographic arthritis and serological and clinical features. The radiographic results indicated that disease duration correlated with joint erosion, acro-osteolysis, resorption of distal ulna, calcinosis and radiologic FC (p< 0.05). Acro-osteolysis was more frequent in the dcSSc subtype, TFRs, and anti-TOPO I antibody. Radiologic FC showed association with skin score, calcinosis and haematocrit <30% (p<0.05). Joint flexion on radiography was associated with disease duration, modified Rodnan skin score, calcinosis, and low haematocrit (P<0.01).Conclusion:Disease duration was a main dependent factor for developing joint erosion, acro-osteolysis, bone resorption, calcinosis, and flexion contracture on hand radiography. Acro-osteolysis presented in the severe form of the disease. Acro-osteolysis was the only dependent variable associated with bone demineralization.

Clinical Manifestation and Incidence of Cardiopulmonary Complications in Early Systemic Sclerosis Patients with Different Antibody Profiles.

BackgroundThere has been no prior inception cohort study comparing clinical manifestations and incidence rate (IR) of cardiopulmonary involvement among early systemic sclerosis (SSc) patients by difference in autoantibody profiles. We compared the differences in the clinical presentation at study entry and cumulative organ complications at last visit, as well as the IR of cardiopulmonary complications between anti-topoisomerase I antibody-positive SSc patients (pATA), ATA-negative (nATA), and the positive anti-centromere antibody patients (pACA).MethodsAn inception cohort of early diagnosis SSc patients (disease duration ≤ 3 years) seen at the Rheumatology Clinic, Maharaj Nakorn Chiang Mai Hospital, between January 2010 and June 2016, was studied. SSc patients who had follow-up duration as less than 1 year and those diagnosed with an overlap syndrome were excluded. All participants underwent electrocardiography (ECG), echocardiography, and high-resolution computed tomography (HRCT) at the study entry and then annually.ResultsA total of 114 patients (90 diffuse cutaneous SSc (dcSSc), 69 women) with mean (standard deviation, SD) disease duration of 11.7 (8.8) months at cohort entry and an observational period of 3.8 (1.6) years, were recruited. There were 89 patients (78.1%) with pATA, 18 (15.8%) with nATA, and 7 (6.1%) with pACA. At enrollment, both pATA and nATA groups had a higher prevalence of dcSSc subtype, and interstitial lung disease (ILD) when compared with the pACA group. At the last visit, the pATA group had a higher cumulative prevalence of digital ulcers, joint contracture and tendon friction rub than the other groups. Both the pATA and nATA groups had a significantly higher IR of ILD compared to the pACA group (54.9 and 57.8 vs. 6.3 per 100 person-years). During the study period, no suspected myositis, systolic pulmonary artery pressure (sPAP) ≥ 50 mm Hg or cardiac complications was observed in the pACA group.ConclusionsIn our study cohort, the majority of which were dcSSc subtype with pATA, it was found that the presence of SSc-specific autoantibodies was associated with a distinctive clinical presentation and cumulative internal organ involvement, even in the early phase of the disease. Cardiopulmonary complications were rarely seen in the pACA group; whereas ILD complications were very common in both the pATA and nATA groups. A further study into the association of autoantibodies in nATA patients with ILD complications is needed.

Survival and prognosis factors in systemic sclerosis: Data of a French multicenter cohort of incident patients, systematic review and meta-analysis of the literature

Introduction Several studies have assessed prognosis factors in systemic sclerosis (SSc), but only few have investigated extensive clinical and laboratory factors in a large, incident and well phenotyped population. The aim of the present study was to describe survival, standardized mortality ratio (SMR) and prognostic factors in a well-phenotyped and multicenter French cohort of incident SSc patients. A systematic review and meta-analysis of cohort studies to assess SMR and prognostic factors in SSc was then performed. Patients and methods Survival, SMR and prognosis factors were assessed in a cohort of SSc patients followed in five referral centers in France. A systematic review of the literature was carried out in Pubmed up to July 2017. Cohort studies of unselected SSc patients reporting SMR and prognostic factors were included in the analysis. We calculated the pooled summary estimates of SMR and hazard ratios (HR) of prognosis factors. Results Out of the 42 referral centers included in the French SSc registry, the present analysis was restricted to 5 centers to ensure the lowest rate of missing data. 625 SSc patients [28.6% of diffuse SSc (dcSSc)] with recent diagnosis were followed from January 2000 to December 2013. Mean age at disease onset was 50.6 ± 14.5 years and mean follow-up was 5.2 ± 3.6 years. In total, 104 deaths were recorded. Overall survival rates at 1, 3, 5 and 10 years from diagnosis were 98.0%, 92.5%, 85.9% and 71.7% respectively. Overall SMR was 5.73 [95% confidence interval (CI) 4.68–6.94]. Age at diagnosis > 60 years, dcSSc, scleroderma renal crisis, severe dyspnoea, FVC 8 mg/L were associated with a poorer survival. Eighteen articles were included in the SMR meta-analysis, representing a total population of 11,329 patients and 33 studies were included in the prognosis factors meta-analysis, representing a total of 23,520 patients. Pooled SMR was 3.45 [IC95% 3.03–3.94]. Age at disease onset, age at diagnosis, male sex, black race, dcSSc subtype, anti-Scl70 autoantibodies, cardiac and renal involvements, interstitial lung disease, PH and malignancy were significantly associated with a worse prognosis. Presence of ACA autoantibodies was associated with a better survival. Conclusion Our study confirms a high mortality rate in SSc and previously described prognosis factors related to skin extension, autoantibody status and organ involvement while reporting new association such as telangiectases and valvular disease.

Toll-like receptor 9 in systemic sclerosis patients: relation to modified Rodnan skin score, disease severity, and functional status.

The objective of this study is to assess toll-like receptor-9 (TLR9) expression in CD3-positive T lymphocytes and CD19-positive B lymphocytes in systemic sclerosis (SSc) patients and to study their relation to the extent of skin fibrosis, disease characteristics, and severity as well as the functional status. Fifty-five female SSc patients and 30 matched controls were included. Skin thickness was scored according to the modified Rodnan skin score (mRss). The severity of major organ involvement was assessed using the Medsger severity score (MSS). Scleroderma health assessment questionnaire (SHAQ) was measured to evaluate patients' functional status. Expression of TLR9 in CD3-positive T lymphocytes and CD19-positive B lymphocytes was studied using flow cytometry. The mean age of the patients was 40.5±9.1years, and their disease duration was 6.7±3.3years. There were 21 (38.2%) with diffuse (dcSSc) and 34 (61.8%) with limited cutaneous (lcSSc) subtypes. There was a significant increase in the expression of TLR9/CD3 and TLR9/CD19 in the SSc patients (44.9±18.1 and 24.1±9.6) compared to that in the control (1.4±0.97 and 1.3±0.94; p<0.0001 for both, respectively) being higher in those with dcSSc. TLR9/CD3 expression was significantly increased in SSc patients with arthralgia/arthritis and digital resorption compared to those without. The TLR9/CD3 significantly correlated with the mRss and MSS (r=0.37, p=0.006 and r=0.31, p=0.02; respectively). Both the TLR9/CD3 and TLR9/CD19 expressions were significantly correlating (r=0.53, p<0.0001). On regression analysis, only TLR9/CD3 was a significant risk factor of the mRss and MSS (β=0.43, p=0.009 and β=0.33, p=0.015, respectively). TLR9, especially TLR9/CD3, is highly expressed in SSc patients particularly those with dcSSc subtype and could form a potential marker for skin fibrosis and disease severity.

Clinical utility of hypo- and hyperpigmentation of skin in diffuse cutaneous systemic sclerosis.

Cutaneous involvement is an early manifestation of systemic sclerosis (SSc). Localized areas of 'salt and pepper skin' (S&P) may develop. We hypothesize that S&P skin occurs frequently in diffuse cutaneous (dc) SSc which can be used in its early diagnosis and may correlate with joint contractures. Sixty-five patients were recruited for this study. The demographic profiles of SSc were ascertained from hospital records. These patients fulfilled the 2013 American College of Rheumatology/European League Against Rheumatism classification criteria. Patients were examined for skin pigmentary changes, modified Rodnan skin score (mRSS), telengiectasias, calcinosis, arthritis and joint contractures and pruritus. Sixty-five patients (59 female) were recruited with median age of 62.87 years. Forty-four had limited cutaneous SSc, 16 dcSSc, five had scleroderma overlap syndrome. Multivariate stepwise logistic regression indicated that mRSS severity and the presence of contractures were independently (P < 0.05) associated with dcSSc. The strong positive association between S&P and mRSS severity may explain the non-significance of S&P in this analysis. If mRSS severity is not included in the logistic regression analysis, the presence of contractures and S&P (odds ratio = 15.1) show significant (P < 0.01) independent associations with the dcSSc subtype. S&P skin and pruritus were similar in patients with Scl-70 and anti-RNA polymerase antibodies. Anti-centromere antibodies were negatively associated with S&P (χ2 = 7.89, P = 0.005). Our study demonstrates strong association of S&P skin with dcSSc (69%), increased risk of pruritus and contractures. Its presence can be used as another clinical tool to diagnose dcSSc in early stages. Observing for S&P skin changes does not require much training.

88 Characterisation of Sub-clinical Primary Myocardial Disease in Systemic Sclerosis – Preliminary Findings from a Cardiac Magnetic Resonance Study

<h3>Background</h3> Systemic sclerosis (SSc) is a chronic disease characterised by systemic inflammation, vasculopathy and fibrosis. Primary myocardial disease occurs in both limited (lcSSc) and diffuse (dcSSc) cutaneous subtypes, and carries a poor prognosis. The natural history is poorly understood, with no clear approach to identifying the ‘at-risk’ patient. CMR studies in SSc have rarely correlated with disease phenotype. <h3>Objectives</h3> To determine cardiovascular manifestations of SSc using multi-component CMR. <h3>Method</h3> Eleven patients fulfilling SSc ACR/Le-Roy criteria, without known CV disease or diabetes, underwent CMR at 3.0T (Philips Achieva TX). Data from 10 healthy subjects served as a control group. Standard bSSFP cine images were acquired and LV dimensions calculated. First-pass perfusion imaging in three short-axis LV slices was performed during administration of 0.1 mmol/kg of gadobutrol at 3 min of 140 mcg/kg/min adenosine for stress and repeated 15 min later at rest. Myocardial perfusion reserve (MPR) was calculated using Fermi deconvolution (PMI v.0.4, [Sourbron, 2009] with basal blood pool providing the arterial input. Native and 15 min post final contrast T1 maps were generated from mid-LV short axis using a modified 3,3,5 Look-Locker inversion sequence to calculate extra-cellular volume (ECV) fraction. <h3>Results</h3> Patient characteristics were as follows: Mean age 54 ± 16, disease duration 9.6 ± 7.3 years, 7 female, 7 lcSSc subtype, 4 dcSSc subtype, 5 interstitial lung disease. Smoking status: 1 current, 8 ex-smoker, 2 never. 3 have known hypertension. CMR measurements are presented in Table 1. One patient with lsSSc subtype showed lateral mid-ventricular wall enhancement on LGE. ECV increased and MPR decreased with age (r = 0.657, p = 0.039; rho= -0.75, p = 0.02 respectively). A non-significant trend for a higher ECV was noted in lcSSc subtype (mean ECV 33% vs. 28% dcSSc subtype, p = 0.14). ECV was similar for disease duration (mean ECV 33% &gt;10 years vs. 30% &lt;10 years, p = 0.2). MPR was non-significantly lower in lcSSc subtype (mean 1.83 vs. 2.13 in dcSSc subtype, p = 0.3) and there was no strong association with disease duration. MPR in SSc was lower than in healthy controls (n = 9) (1.9 vs. 2.8, p = 0.03). <h3>Conclusion</h3> CMR demonstrates lower MPR in patients with SSc than in controls. Our preliminary data suggest that quantitative CMR may also be able to detect differences in myocardial involvement in subtypes of the disease, justifying future larger studies.

Asymptomatic cardiac involvement in Thai systemic sclerosis: prevalence and clinical correlations with non-cardiac manifestations (preliminary report).

To determine the prevalence of asymptomatic cardiac involvement and its correlation with non-cardiac manifestation in Thai SSc patients. A cross-sectional study was carried out between January 2012 and June 2013 at Srinagarind Hospital, Khon Kaen University, Thailand, on adult SSc patients without signs or symptoms suggestive of cardiac involvement. We excluded those with overlap syndrome, having serum creatinine >123.8 µmol/l, history of cardiac diseases, any atherosclerosis risk factors and receiving angiotensin-converting enzyme inhibitors. Non-invasive tests related to cardiac involvement were performed, including: echocardiography, ECG, chest X-ray, inflammatory biomarkers, cardiac enzymes and N-terminal prohormone of brain natriuretic peptide. A total of 103 SSc patients were enrolled, 61.2% of whom were in the subset. Of these, 63 patients had at least one test abnormality (prevalence 61.2%; 95% CI 51.6, 70.7). The two leading cardiac abnormalities were diastolic dysfunction (44.7%) and elevation of cardiac enzymes (36.9%). The only predictor for cardiac involvement per multivariate analysis was the dcSSc subtype with a higher modified Rodnan skin score, and shorter disease duration (odds ratio = 3.37; 95% CI 1.07, 10.65). Compared with the limited subtype, dcSSc was also significantly associated with elevated cardiac enzyme and prolonged distance between a Q wave and T wave in an ECG (QT interval). Asymptomatic cardiac involvement in Thai SSc was not uncommon, and the most common finding was diastolic dysfunction. Elevated cardiac enzymes were found in one-third of the patients, which correlated with the dcSSc subtype with a higher modified Rodnan skin score and shorter disease duration, suggestive of early myocardial microcirculation disruption. Long-term follow-up was performed to elucidate the clinical implication of these abnormalities.

Demographic and clinical features of systemic sclerosis patients with anti-RNA polymerase III antibodies.

Anti-RNA polymerase III antibody (RNAP) is primarily detected in diffuse cutaneous type systemic sclerosis (dcSSc) patients and strongly associated with renal crisis. Additionally, there has been increasing evidence that cancer in SSc patients is associated with RNAP. The aim of this study was to examine the demographic and clinical features of SSc patients with RNAP. Among 246 SSc patients, 5.7% were positive for RNAP, 20.7% were positive for anti-topoisomerase I antibody (Topo I) alone and 39.4% were positive for anticentromere antibody (ACA) alone. The modified Rodnan total skin score (mRTSS) in SSc patients with RNAP (19.1±2.6) was significantly higher than those in SSc patients with Topo I (11.5±1.1) and patients with ACA (4.4±0.4). Furthermore, among SSc patients with RNAP, the levels of RNAP were positively correlated with mRTSS. Renal crisis is also significantly more prevalent in SSc patients with RNAP than patients without RNAP. Male sex, dcSSc subtype, digital vasculopathy, including digital ulcers and acro-osteolysis, interstitial lung disease and rheumatoid arthritis complications were prevalent in SSc patients with RNAP and patients with Topo-I. Primary biliary cirrhosis and Sjögren's syndrome were more in SSc patients with RNAP and patients with ACA compared with patients with Topo 1. No significant difference in the frequency of complications, including Raynaud's phenomenon, pulmonary artery hypertension and malignancy was observed between the three groups. Thus, measurement of RNAP in SSc patients is useful for the diagnosis and risk stratification of severe manifestation, such as renal crisis and severe skin sclerosis.

C8orf13-BLK is a genetic risk locus for systemic sclerosis and has additive effects with BANK1: Results from a large french cohort and meta-analysis

Accumulating evidence suggests that B cells are involved in systemic sclerosis (SSc). BANK1 has been reproducibly reported to be associated with diffuse cutaneous SSc (dcSSc). BLK encodes another B cell signal transducer, and a functional variant at the C8orf13-BLK locus has been found to be associated with SSc in Caucasians. However, no independent replication has been reported, and there are discrepancies in the genotype-phenotype correlation between these studies in Caucasians and another study performed in the Japanese population. Therefore, in a large cohort of French Caucasians and using a meta-analysis of the available data, this study was undertaken to determine whether the C8orf13-BLK locus is associated with SSc, and to assess the possibility of interaction between BLK and BANK1 in SSc. The C8orf13-BLK rs13277113 genotype was determined in 1,031 patients with SSc and 1,014 control subjects for whom BANK1 genotypes were available. Meta-analysis of the 3 available data sets (6,078 individuals) was also performed. Minor allele frequencies for rs13277113 revealed an association restricted to the dcSSc subtype (P = 0.012, odds ratio [OR] 1.29) in the French sample. Meta-analysis of the combined Caucasian populations showed an association of this genotype with both SSc (P = 0.0013, OR 1.16, 95% confidence interval [95% CI] 1.06-1.26) and dcSSc (P = 0.0012, OR 1.23, 95% CI 1.08-1.39). Inclusion of the Japanese population confirmed the overall association with the disease, with the strongest association observed with dcSSc (P = 3.27 × 10⁻⁵, OR 1.27). Secondary analysis in the French sample revealed additive effects between C8orf13-BLK and BANK1, mainly in the dcSSc subset. These results confirm C8orf13-BLK as an SSc risk locus. The strongest effects, and particularly additive effects, were observed in the interaction between C8orf13-BLK and BANK1 in the dcSSc subset.

Expression of advanced glycation end products and their receptor in skin from patients with systemic sclerosis with and without calcinosis

Our aim was to establish which tissue components express advanced glycation/lipoperoxidation end products (AGEs) and their receptor (RAGE) in skin from patients with SSc, and how their expression relates to the disease subtypes and various clinical parameters. Skin punch biopsies were taken from the forearms of 61 SSc patients with lcSSc; 32 with calcinosis (lcSScCal) and 29 without lcSSc, 36 with the dcSSc subtype and 22 healthy control subjects. Immunohistochemical localization of AGE-CML [N(epsilon)-(carboxymethyl) lysine] and RAGE was assessed semi-quantitatively on the microvascular endothelium, dermal fibroblasts and the cutaneous extracellular matrix (ECM). The Kruskal-Wallis one-way ANOVA was used to compare data between groups. AGE-CML expression on the papillary dermis ECM of lcSScCal was greater than in the control group (P = 0.016). The reticular dermis of lcSScCal showed increased AGE-N(epsilon)-(carboxymethyl) lysine (CML) expression compared with controls (P = 0.002), dcSSc (P = 0.024) and lcSSc (P = 0.025). Increased immunostaining for RAGE was seen on the reticular dermis ECM of the lcSScCal group compared with controls (P = 0.007). The lcSScCal subgroup showed statistically significant correlations for AGE-CML, and to a lesser extent for RAGE, with increased RP duration. There was no consistent evidence that the expression of AGE-CML or RAGE related to autoantibody status, clinical or histological skin score or patient age. Our results indicate the possible contribution of AGE-CML deposition on the ECM in the dermis of the lcSScCal subgroup to the pathogenesis of formation of calcinotic deposits.