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.

Assess whether treatment with probiotics improve gastrointestinal symptoms in patients with systemic sclerosis (SSc). In this double-blind randomized placebo-controlled parallel-group phase II trial, SSc subjects with total score ≥ 0.1 on a validated SSc-specific gastrointestinal tract (GIT) questionnaire were randomized (1:1) to receive 60 days of high dose multi-strain probiotics (Vivomixx® 1800 billion units/day) or identical placebo, followed by an additional 60 days of probiotics in both groups. Between group differences in GIT score change were assessed after 60 days (primary outcome, time-point T1) and 120 days (secondary outcome, time-point, T2) by an intention-to-treat approach. Stool samples at three time-points were subjected to 16S next generation sequencing. Forty subjects were randomized to placebo-probiotics (n = 21) or probiotics-probiotics (n = 19). At T1, no significant improvement was observed between the two groups, reported as mean ± SE for total GIT score (placebo 0.14 ± 0.06 versus probiotics 0.13 ± 0.07; p = 0.85) or its subdomains. At T2, whilst there was no significant improvement in total GIT score (placebo-probiotics -0.05±0.06; probiotics-probiotics -0.18 ± 0.07; p = 0.14), there was significant improvement of GIT-reflux in the probiotic group (-0.22 ± 0.05 versus placebo-probiotics 0.05 ± 0.07; p = 0.004). Subjects on probiotics exhibited increasing stool microbiota alpha diversity compared to the placebo-probiotics group. Adverse events (AEs) were mild, with similar proportion of subjects with AEs and serious AEs in both groups. Whilst there was no clear improvement in overall GI symptoms after 60 days, we observed significantly improved GI reflux after 120 days of probiotics. The trial confirmed safety of multi-strain probiotics in SSc patients. Clinicaltrials.gov; NCT01804959.

Single-cell RNA sequencing (scRNA-seq) has emerged as a powerful technique for investigating biological heterogeneity at the single-cell level in human systems and model organisms. Recent advances in scRNA-seq have enabled the pooling of cells from multiple samples into single libraries, thereby increasing sample throughput while reducing technical batch effects, library preparation time, and the overall cost. However, a comparative analysis of scRNA-seq methods with and without sample multiplexing is lacking. In this study, we benchmarked methods from two representative platforms: Parse Biosciences (Parse; with sample multiplexing) and 10x Genomics (10x; without sample multiplexing). By using peripheral blood mononuclear cells (PBMCs) obtained from two healthy individuals, we demonstrate that demultiplexed scRNA-seq data obtained from Parse showed similar cell type frequencies compared to 10x data where samples were not multiplexed. Despite relatively lower cell capture affecting library preparation, Parse can detect rare cell types (e.g., plasmablasts and dendritic cells) which is likely due to its relatively higher sensitivity in gene detection. Moreover, a comparative analysis of transcript quantification between the two platforms revealed platform-specific distributions of gene length and GC content. These results offer guidance for researchers in designing high-throughput scRNA-seq studies.

Aim: People with rheumatic diseases (PRD) remain vulnerable in the era of the COVID‐19 pandemic. We formulated recommendations to meet the urgent need for a consensus for vaccination against SARS‐CoV‐2 in PRD.Methods: Systematic literature reviews were performed to evaluate: (a) outcomes in PRD with COVID‐19; (b) efficacy, immunogenicity and safety of COVID‐19 vaccination; and (c) published guidelines/recommendations for non‐live, non‐COVID‐19 vaccinations in PRD. Recommendations were formulated based on the evidence and expert opinion according to the Grading of Recommendations Assessment, Development and Evaluation methodology.Results: The consensus comprises 2 overarching principles and 7 recommendations. Vaccination against SARS‐CoV‐2 in PRD should be aligned with prevailing national policy and should be individualized through shared decision between the healthcare provider and patient. We strongly recommend that eligible PRD and household contacts be vaccinated against SARS‐CoV‐2. We conditionally recommended that the COVID‐19 vaccine be administered during quiescent disease if possible. Immunomodulatory drugs, other than rituximab, can be continued alongside vaccination. We conditionally recommend that the COVID‐19 vaccine be administered prior to commencing rituximab if possible. For patients on rituximab, the vaccine should be administered a minimum of 6 months after the last dose and/or 4 weeks prior to the next dose of rituximab. Post‐vaccination antibody titers against SARS‐CoV‐2 need not be measured. Any of the approved COVID‐19 vaccines may be used, with no particular preference.Conclusion: These recommendations provide guidance for COVID‐19 vaccination in PRD. Most recommendations in this consensus are conditional, reflecting a lack of evidence or low‐level evidence.

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]. 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. 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. 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.