The Pathogenesis of Systemic Sclerosis: The Origin of Fibrosis and Interlink with Vasculopathy and Autoimmunity.

Systemic sclerosis (SSc) is an autoimmune disease associated with increased mortality and poor morbidity, impairing the quality of life in patients. Whilst we know that SSc affects multiple organs via vasculopathy, inflammation, and fibrosis, its exact pathophysiology remains elusive. Microvascular injury and vasculopathy are the initial pathological features of the disease. Clinically, the vasculopathy in SSc is manifested as Raynaud's phenomenon (reversible vasospasm in reaction to the cold or emotional stress) and digital ulcers due to ischemic injury. There are several reports that medications for vasculopathy, such as bosentan and soluble guanylate cyclase (sGC) modulators, improve not only vasculopathy but also dermal fibrosis, suggesting that vasculopathy is important in SSc. Although vasculopathy is an important initial step of the pathogenesis for SSc, it is still unclear how vasculopathy is related to inflammation and fibrosis. In this review, we focused on the clinical evidence for vasculopathy, the major cellular players for the pathogenesis, including pericytes, adipocytes, endothelial cells (ECs), and myofibroblasts, and their signaling pathway to elucidate the relationship among vasculopathy, inflammation, and fibrosis in SSc.

Toward Molecular Stratification and Precision Medicine in Systemic Sclerosis.

Systemic sclerosis (SSc), a complex multi-systemic disease characterized by immune dysregulation, vasculopathy and fibrosis, is associated with high mortality. Its pathogenesis is only partially understood. The heterogenous pathological processes that define SSc and its stages present a challenge to targeting appropriate treatment, with differing treatment outcomes of SSc patients despite similar initial clinical presentations. Timing of the appropriate treatments targeted at the underlying disease process is critical. For example, immunomodulatory treatments may be used for patients in a predominantly inflammatory phase, anti-fibrotic treatments for those in the fibrotic phase, or combination therapies for those in the fibro-inflammatory phase. In advancing personalized care through precision medicine, groups of patients with similar disease characteristics and shared pathological processes may be identified through molecular stratification. This would improve current clinical sub-setting systems and guide personalization of therapies. In this review, we will provide updates in SSc clinical and molecular stratification in relation to patient outcomes and treatment responses. Promises of molecular stratification through advances in high-dimensional tools, including omic-based stratification (transcriptomics, genomics, epigenomics, proteomics, cytomics, microbiomics) and machine learning will be discussed. Innovative and more granular stratification systems that integrate molecular characteristics to clinical phenotypes would potentially improve therapeutic approaches through personalized medicine and lead to better patient outcomes.

The microbiome and systemic sclerosis: A review of current evidence.

Systemic sclerosis (SSc) is characterized by immune dysregulation, vasculopathy, and fibrosis of multiple organs. The gastrointestinal (GI) tract is the most common internal organ manifestation, which contributes to significant morbidity and mortality in patients with SSc. Emerging reports have identified unique microbial taxa alterations in the GI microbiome of patients with SSc as compared to healthy controls (HC). These taxa alterations include differences at the phyla (e.g., Bacteroidetes) and genera (e.g., Bacteroides, Clostridium, Faecalibacterium, and Lactobacillus) level. In addition, some genera have been associated with more severe GI symptoms (e.g., Prevotella and Akkermansia). This review summarizes the current evidence on factors influencing the GI microbiome, GI microbiome alterations in SSc as compared to HC, and in SSc subgroups according to disease manifestations. Current exploration in therapeutic interventions that target the GI microbiome is discussed.

Choosing the right treatment for patients with psoriatic arthritis.

Psoriatic arthritis (PsA) is a chronic inflammatory condition with articular and extra-articular manifestations: peripheral arthritis, axial disease, enthesitis, dactylitis, psoriasis, inflammatory bowel disease and uveitis. Anti-tumour necrosis factors (anti-TNFs) have demonstrated clinical efficacies exceeding those of conventional disease-modifying antirheumatic drugs (DMARDs). New understanding in pathogenic pathways have led to novel therapeutic targets. The current treatment paradigms emphasize early diagnosis and treatment, and treating towards remission and low disease activity status, particularly in long-standing disease. This review addresses the evidence of current treatment options for each of the domains of PsA. We present a simple guide that weighs on clinical efficacies for each PsA domain to aid clinicians in choosing the most appropriate treatment for patients. We highlight the unmet need for biomarkers of treatment response, and future perspectives with precision medicine in PsA.

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.

Validation of screening questionnaires for evaluation of knee osteoarthritis prevalence in the general population of Singapore.

BACKGROUND: The prevalence of symptomatic knee osteoarthritis (KOA) in Singapore is unknown. We aimed to: (i) validate questionnaires to screen for symptomatic KOA; and (ii) estimate the prevalence of symptomatic KOA in Singapore using the validated algorithms. METHODS: Subjects aged ≥50 years were evaluated for symptomatic KOA based on American College of Rheumatology clinical and radiographic criteria in a rheumatology clinic, and completed three sets of adapted screening questionnaires. The better performing screening questionnaire with adequate sensitivity and specificity was adminitered to a nationally representative sample of survey subjects (n = 3364) to estimate the weighted prevalence of symptomatic KOA in Singapore. RESULTS: Out of 146 subjects evaluated in the clinic, 45 had symptomatic KOA. A screening algorithm which consisted of three KOA symptoms or one symptom plus physician-diagnosed KOA produced high specificity (0.95, 95% confidence intervals [CI]: 0.88-0.98) but low sensivity (0.44, 95% CI: 0.30-0.60). Replacing the term 'KOA' with 'physician-diagnosed ageing-related knee problem' improved the sensivity (0.62, 95% CI: 0.47-0.76) without significantly compromising the specificity (0.87, 95% CI: 0.79-0.93). The prevalence of symptomatic KOA weighted to the Singapore population distribution were 4.7% and 11%, using the most conservative and more liberal algorithms, respectively. There was a sharp rise in prevalence after age of 40. The weighted prevalence of KOA was higher in women and among Indian and Malay than Chinese. CONCLUSION: Our study adapted and validated questionnaires to the local context to screen for symptomatic KOA. We estimated the prevalence of symptomatic KOA in Singapore utilizing the better-performing algorithms.

Point-of-Care Rapid-Seeding Ventricular Assist Device with Blood-Derived Endothelial Cells to Create a Living Antithrombotic Coating.

The most promising alternatives to heart transplantation are left ventricular assist devices and artificial hearts; however, their use has been limited by thrombotic complications. To reduce these, sintered titanium (Ti) surfaces were developed, but thrombosis still occurs in approximately 7.5% of patients. We have invented a rapid-seeding technology to minimize the risk of thrombosis by rapid endothelialization of sintered Ti with human cord blood-derived endothelial cells (hCB-ECs). Human cord blood-derived endothelial cells were seeded within minutes onto sintered Ti and exposed to thrombosis-prone low fluid flow shear stresses. The hCB-ECs adhered and formed a confluent endothelial monolayer on sintered Ti. The exposure of sintered Ti to 4.4 dynes/cm for 20 hr immediately after rapid seeding resulted in approximately 70% cell adherence. The cell adherence was not significantly increased by additional ex vivo static culture of rapid-seeded sintered Ti before flow exposure. In addition, adherent hCB-ECs remained functional on sintered Ti, as indicated by flow-induced increase in nitric oxide secretion and reduction in platelet adhesion. After 15 day ex vivo static culture, the adherent hCB-ECs remained metabolically active, expressed endothelial cell functional marker thrombomodulin, and reduced platelet adhesion. In conclusion, our results demonstrate the feasibility of rapid-seeding sintered Ti with blood-derived hCB-ECs to generate a living antithrombotic surface.

Point-of-care seeding of nitinol stents with blood-derived endothelial cells.

Nitinol-based vascular devices, for example, peripheral and intracranial stents, are limited by thrombosis and restenosis. To ameliorate these complications, we developed a technology to promote vessel healing by rapidly seeding (QuickSeeding) autologous blood-derived endothelial cells (ECs) onto modified self-expanding nitinol stent delivery systems immediately before implantation. Several thousand micropores were laser-drilled into a delivery system sheath surrounding a commercial nitinol stent to allow for exit of an infused cell suspension. As suspension medium flowed outward through the micropores, ECs flowed through the delivery system attaching to the stent surface. The QuickSeeded ECs adhered to and spread on the stent surface following 24-h in vitro culture under static or flow conditions. Further, QuickSeeded ECs on stents that were deployed into porcine carotid arteries spread to endothelialize stent struts within 48 h (n = 4). The QuickSeeded stent struts produced significantly more nitric oxide in ex vivo flow circuits after 24 h, as compared to static conditions (n = 5). In conclusion, ECs QuickSeeded onto commercial nitinol stents within minutes of implantation spread to form a functional layer in vitro and in vivo, providing proof of concept that the novel QuickSeeding method with modified delivery systems can be used to seed functional autologous endothelium at the point of care. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 104B: 1658-1665, 2016.

Increased yield of endothelial cells from peripheral blood for cell therapies and tissue engineering.

AIM: Peripheral blood-derived endothelial cells (pBD-ECs) are an attractive tool for cell therapies and tissue engineering, but have been limited by their low isolation yield. We increase pBD-EC yield via administration of the chemokine receptor type 4 antagonist AMD3100, as well as via a diluted whole blood incubation (DWBI). MATERIALS & METHODS: Porcine pBD-ECs were isolated using AMD3100 and DWBI and tested for EC markers, acetylated LDL uptake, growth kinetics, metabolic activity, flow-mediated nitric oxide production and seeded onto titanium tubes implanted into vessels of pigs. RESULTS: DWBI increased the yield of porcine pBD-ECs 6.6-fold, and AMD3100 increased the yield 4.5-fold. AMD3100-mobilized ECs were phenotypically indistinguishable from nonmobilized ECs. In porcine implants, the cells expressed endothelial nitric oxide synthase, reduced thrombin-antithrombin complex systemically and prevented thrombosis. CONCLUSION: Administration of AMD3100 and the DWBI method both increase pBD-EC yield.