Biomarkers in the evaluation of cardiac involvement in systemic sclerosis.

Systemic sclerosis is a multisystemic disease for which the heart can be affected leading to cardiac complications and mortality. Up to 80% of patients with systemic sclerosis have cardiac involvement with varying levels of severity. Several molecules have been identified that can be used as markers of cardiac involvement. These biomarkers can arise directly from the heart due to cardiac damage from the disease such as cardiac troponins or from the underlying dysregulated immune process itself such as the proinflammatory cytokines including interleukin (IL)-6. This review aims to summarize the evidence on currently known biomarkers that are can be diagnostic, prognostic or predictive of primary cardiac involvement in systemic sclerosis. We also highlight potential new biomarkers based on the current understanding of the disease process. Clinical use of these markers can benefit patients through earlier identification of those with cardiac involvement, many of whom can be asymptomatic in the early stage, with higher risk of complications, with the overall goal to improve outcomes of these affected patients.

Evaluation of Nailfold Capillaroscopy Online Training Using the Fast Track Algorithm.

OBJECTIVE: Nailfold capillaroscopy (NFC) is increasingly used in the early identification of systemic sclerosis (SSc)-related disorders. A consensus "Fast Track algorithm" was developed by the European Alliance of Associations for Rheumatology to aid differentiation of scleroderma from nonscleroderma pattern on NFC. Our objective was to evaluate the online training of NFC using the Fast Track algorithm in the assessment of scleroderma vs nonscleroderma NFC pattern. METHODS: Participants attended the NFC online training workshop and were taught the Fast Track algorithm. Following the training, participants independently evaluated 45 NFC images in the same session, and then 2 to 4 weeks later, through the online platform. Participants had to differentiate between scleroderma vs nonscleroderma pattern, and additionally nonscleroderma pattern (normal) vs nonscleroderma pattern (nonspecific). The inter- and intrarater Cohen [Formula: see text] agreement was calculated. RESULTS: Ninety-eight participants took part in the baseline evaluation, and 61 in the reevaluation session. For identification of scleroderma vs nonscleroderma pattern, the mean (95% CI) inter- and intrarater [Formula: see text] were 0.86 (0.83-0.88) and 0.83 (0.79-0.87), respectively. The overall inter- and intrarater [Formula: see text] in the identification of scleroderma, nonscleroderma (normal), and nonscleroderma (nonspecific) patterns were 0.71 (0.69-0.74) and 0.71 (0.67-0.75), respectively. For nonscleroderma (normal) vs nonscleroderma (nonspecific) pattern, the inter- and intrarater [Formula: see text] were 0.59 (0.55-0.63) and 0.59 (0.54-0.65), respectively. CONCLUSION: In this first study evaluating NFC online training using the Fast Track algorithm, we showed very good inter- and intrarater agreement for the identification of scleroderma and nonscleroderma NFC pattern, supporting the feasibility of online NFC standardized training workshops.

Systemic sclerosis in Asians: Are there racial differences?

Systemic sclerosis is a multisystemic autoimmune disease characterized by vasculopathy and fibrosis. Racial factors exert a significant influence on the epidemiology, clinical manifestations, antibody profile, mortality and genetic factors in systemic sclerosis. In this review, we examined Asian systemic sclerosis cohorts reported in Asia and multi-racial cohort studies to evaluate the disease characteristics and outcomes of systemic sclerosis in Asians. Asian patients have distinct genetic susceptibility to systemic sclerosis, younger age of systemic sclerosis onset, higher frequency of diffuse skin involvement, different autoantibody profiles such as higher frequency of anti-Scl70 and anti-U1-RNP antibodies, and more severe clinical phenotype. There was a suggestion of poorer survival among Asians that may be contributed by more severe disease, socioeconomic factors and differences in healthcare systems. Recognizing the influence of racial differences in systemic sclerosis disease course is important as it has implications for appropriate treatment, monitoring and prognostication.

Mortality and hospitalization outcomes of interstitial lung disease and pulmonary hypertension in the Singapore systemic sclerosis cohort.

OBJECTIVES: We compared mortality and hospitalization rates in four groups of patients with systemic sclerosis (SSc) [isolated pulmonary arterial hypertension (PAH) or interstitial lung disease (ILD), concomitant ILD-pulmonary hypertension (PH), and no/mild pulmonary involvement]. METHODS: In the Systemic Sclerosis Cohort Singapore (SCORE), ILD was diagnosed by HRCT and significant ILD was defined by forced vital capacity <70% predicted. Patients were classified as PAH if echocardiographic systolic pulmonary artery pressure (sPAP) ≥50 mmHg or right heart catheterization (RHC) mean PAP ≥25 mmHg. Multivariable regression analyses were performed to determine factors associated with mortality and hospital admissions per year. Cox proportional hazard model was used to analyze survival. RESULTS: Of 490 SSc patients, 50 patients had PAH, 92 patients had ILD and 43 patients had ILD-PH. Of 93 patients with PAH or ILD-PH, 56 were based on echocardiography and 37 on RHC. Patients with ILD-PH (HR 3.77, 95% CI: 2.05-6.93) had the highest risk of death, followed by PAH (HR 3.03, 95% CI: 1.60-5.76) and ILD (HR 1.84, 95% CI: 1.04-3.28). After adjustment for confounders, PAH (HR 2.39, 95% CI: 1.13-5.07) remained independently associated with mortality, but not ILD-PH or ILD. Other factors associated with mortality were male gender, age at SSc diagnosis, malabsorption and digital ulcer/ gangrene. Increased hospitalization rate was associated with renal crisis, right heart failure and PAH medications, but not SSc groups. CONCLUSION: PAH is an independent risk factor of mortality in SSc. Increased hospitalization rate was not associated with SSc groups. Other factors associated with increased mortality and hospital admissions were identified.

Application of stem cell transplantation in autoimmune diseases.

PURPOSE OF REVIEW: Autologous hematopoietic stem cell transplantation (HSCT) is a promising therapeutic modality for severe autoimmune diseases. In this review, we will outline the immunological mechanisms and the clinical evidence and experiences for therapeutic HSCT in autoimmune diseases, with particular focus on systemic sclerosis and multiple sclerosis. RECENT FINDINGS: Approximately 3000 patients with autoimmune diseases worldwide have been treated with HSCT. HSCT in systemic sclerosis has been shown in three randomized controlled trials to be associated with significant long-term event-free survival despite some transplant-related mortality in the first year. A recent controlled trial in multiple sclerosis has also show benefit with transplant. SUMMARY: The aim of HSCT is to 'reset' one's immune system into a naïve and self-tolerant state through immune depletion and regulation. HSCT requires careful patient selection, close collaboration between physicians and expertise of transplant team to ensure optimal outcome.

Evaluation of Scleroderma Clinical Trials Consortium training recommendations on modified Rodnan skin score assessment in scleroderma.

AIM: The modified Rodnan skin score (mRSS) is a validated outcome measure for skin thickness in systemic sclerosis (SSc). Training has been shown to reduce variability in the measurement of mRSS. Our objective was to assess the inter- and intra-observer variability of mRSS scoring using the proposed recommendations for training by the Scleroderma Clinical Trials Consortium (SCTC) and World Scleroderma Foundation (WSF). METHOD: Fifty-two trainees and eight adult SSc patients participated in the SSc skin scoring workshop that was conducted in two sessions by four teachers. Each session, attended by 26 trainees, had a teaching and evaluation phase. The teaching phase comprised of: (a) lecture on mRSS scoring; (b) video demonstration of mRSS scoring; and (c) live demonstration of mRSS on one SSc patient. In the evaluation phase, each trainee independently assessed the mRSS in four SSc patients. For intra-observer reliability, 14 trainees re-assessed the mRSS of two SSc patients whom they had previously examined. We computed the inter- and intra-observer variability using a linear mixed model. RESULTS: For the evaluation phase, 34 (65.4%) trainees were within five units of the established teachers' score in 3 out of 4 patients. Overall, the whole group had acceptable inter-observer variability (intra-class correlation coefficient [ICC] = 0.71, mean = 8.64 and within-patient standard deviation [SD] = 4.25). The intra-observer ICC was 0.85 and within-patient SD was 2.73. CONCLUSION: There was good inter-observer and excellent intra-observer reliability. This is the first study examining the training of assessors using the SCTC/WSF recommendations and our results support the importance of standardized training for skin scoring.

18F-FDG PET-MRI with T1 MOLLI mapping to detect systemic sclerosis bowel inflammation and fibrosis.

BACKGROUND: Systemic sclerosis-associated gastrointestinal tract involvement (SSc-GIT) is an independent predictor of 2-year mortality in early SSc. Availability of non-invasive investigations will facilitate early diagnosis and monitoring. HYPOTHESIS: We investigate the role of 18F-FDG-PET-MRI in SSc-GIT, hypothesizing that i) higher bowel FDG-PET uptake, a surrogate biomarker for inflammation, distinguishes healthy bowel from inflamed SSc-GIT; ii) MRI T1-MOLLI mapping, a surrogate biomarker for cardiac fibrosis, distinguishes healthy bowel from fibrotic SSc-GIT. METHODS: In this prospective study, 16 SSc patients and 15 healthy controls were recruited. All SSc patients and 5 controls underwent PET-MRI (with T1-MOLLI mapping) on a Siemens 3T mMR; 10 controls underwent MRI without PET. Manual segmentation of the large and small bowels was performed jointly by two trained analysts in order to report T1 and PET values. Control dataset was used to assess normal healthy range. Mean T1 values, mean Tissue-to-Background (TBR) PET values, as well as amount of supposedly abnormal bowel (measured using the healthy ranges) was compared using Student's t-test and Cohen's d effect size. RESULTS: Mean T1 values in large (1113 ±â€¯182 ms vs 856 ±â€¯176 ms; p-value < 0.001) and small bowel (1331 ±â€¯239 ms vs 1169 ±â€¯118 ms; p = 0.02) were higher in SSc patients than controls. 87.5% of the SSc patients' bowel had at least a grade 3 segmental FDG-PET uptake, while no controls showed more than a grade 2 segmental uptake. Patients had higher large bowel mean PET TBR (1.12 ±â€¯0.22) than controls (0.82 ±â€¯0.20, p = 0.02). Using PET and T1 thresholds defined using the control PET-MR data, the percentage of supposedly healthy (non-fibrotic and non-inflamed) tissue was significantly lower in SSc patients (81.1 ±â€¯13.1%) than controls (95.7 ±â€¯3.1%, p = 0.03) for the large bowel. CONCLUSION: Our novel study of FDG-PET-MRI in SSc-GIT demonstrated promising results in non-invasively evaluating concurrently bowel inflammation and fibrosis.

Hepatitis B virus X gene and hepatocarcinogenesis.

Chronic hepatitis B virus (HBV) infection has been identified as a major risk factor in hepatocellular carcinoma (HCC), which is one of the most common cancers worldwide. The pathogenesis of HBV-mediated hepatocarcinogenesis is, however, incompletely understood. Evidence suggests that the HBV X protein (HBx) plays a crucial role in HCC development. HBx is a multifunctional regulator that modulates transcription, signal transduction, cell cycle progression, apoptosis, protein degradation pathways, and genetic stability through interaction with host factors. This review describes the current state of knowledge of the molecular pathogenesis of HBV-induced HCC, with a focus on the role of HBx in hepatocarcinogenesis.