BACKGROUND: Systemic sclerosis (SSc) is an autoimmune disease (AD), that receives less attention compared to rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and primary Sjögren\'s syndrome (pSS). This study aims to analyze transcriptional profiles and immune cell composition in peripheral blood mononuclear cells (PBMC) from SSc patients compared to other ADs.
METHODS: RNA-seq data from 119 untreated patients (eight with SSc, 42 with RA, 41 with pSS, 28 with SLE) and 20 healthy controls were analyzed. Bioinformatics tools were employed to identify differentially expressed genes (DEGs), biological functions and immune cell profiles unique to SSc and shared with other ADs.
RESULTS: 1,148 DEGs were found in SSc, with upregulated genes associated with megakaryocyte processes and downregulated genes associated with neutrophil function and immune response. DEGs, including ALDH1A1 and MEGF9, were associated with neutropenia. Upregulated transcription factors (TFs) were linked to embryonic hematopoiesis and downregulated TFs were involved in leukocyte differentiation and immune regulation. Comparative analysis with other ADs revealed common pathogenic pathways, emphasizing megakaryocyte proliferation. Neutrophils count was significantly decreased in ADs (p < 0.001) compared to healthy controls. Comparative analysis highlighted common pathways, particularly in megakaryocyte proliferation, and unique genes (MEGF9, MMP8, and KRT family members) in SSc, suggesting roles in neutrophil function, skin integrity, and fibrosis.
CONCLUSIONS: This study identifies dysregulated gene expression (KRT and MMP8) associated with neutrophil function and increased megakaryocytes in SSc, highlighting common patterns across autoimmune diseases. These findings offer new insights into the potential pathogenesis of SSc, and help to explore new targets for the treatment.

The use of artificial intelligence (AI) in high-resolution computed tomography (HRCT) for diagnosing systemic sclerosis-associated interstitial lung disease (SSc-ILD) is relatively limited. This study aimed to analyse lung HRCT images of patients with systemic sclerosis with interstitial lung disease (SSc-ILD) using artificial intelligence (AI), conduct correlation analysis with clinical manifestations and prognosis, and explore the features and prognosis of SSc-ILD. Overall, 72 lung HRCT images and clinical data of 58 patients with SSC-ILD were collected. ILD lesion type, location, and volume on HRCT images were identified and evaluated using AI. The imaging characteristics of diffuse SSC (dSSc)-ILD and limited SSc-ILD (lSSc-ILD) were statistically analysed. Furthermore, the correlations between lesion type, clinical indicators, and prognosis were investigated. dSSc and lSSc were more prevalent in patients with a disease duration of < 1 and ≥ 5 years, respectively. SSc-ILD mainly comprises non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), and unclassifiable idiopathic interstitial pneumonia. HRCT reveals various lesion types in the early stages of the disease, with an increase in the number of lesion types as the disease progresses. Lesions appearing as grid, ground-glass, and nodular shadows were dispersed throughout both lungs, while those appearing as consolidation shadows and honeycomb were distributed across the lungs. Ground-glass opacity lesion type was absent on HRCT images of patients with SSc-ILD and pulmonary hypertension. This study showed that AI can efficiently analyse imaging characteristics of SSc-ILD, demonstrating its potential to learn from complex images with high generalisation ability.

Systemic sclerosis (SSc) is a typical fibrotic disease of unknown etiology, which is characterized by abnormal fibroblast activation and excessive deposition of extracellular matrix. Unfortunately, effective therapeutic approaches are lacking. Fibroblast growth factor 21 (FGF21) plays a key role in mediating a variety of biological activities. However, its specific function in SSc is unclear. In this study, we found that the expression of FGF21 was significantly downregulated in fibrotic skin tissue and in transforming growth factor-β (TGF-β) stimulated fibroblasts. Furthermore, our studies demonstrated that treatment with recombinant FGF21 in the skin significantly alleviated bleomycin (BLM)-induced and TGF-β receptor I (TBRI)-activated fibrosis and inhibited the activation of fibroblasts, while skin fibrosis was exacerbated by deletion of FGF21. Mechanistically, FGF21 inhibits the activity of CK2α and promotes the degradation of GLI2. In conclusion, these results indicate that FGF21 attenuates skin fibrosis via the CK2α/GLI2 signaling pathway and therefore may be a potential therapeutic target for systemic sclerosis.

Prior evidence suggests that altered energy metabolism plays a crucial role in the development of fibrotic diseases. Recent research indicates that systemic sclerosis (SSc) patients have potentially benefited from energy management, implying that basal metabolic rate (BMR), a vital energy metabolic parameter, may be related to SSc. However, the causal effect of BMR on SSc remains unknown. Thus, we aimed to elucidate the causal links between BMR and SSc. Based on summary statistics from the genome-wide association studies (GWAS) database, two-sample Mendelian randomization (MR) was applied to explore causality between BMR and SSc. The causal relationships were assessed employing inverse variance weighted (IVW), MR-Egger, and weighted median (WM) methods. Meanwhile, several sensitivity analyses were carried out to ensure the robustness of the findings. There was an underlying genetic association of BMR on SSc (OR = 0.505, 95% CI: 0.272-0.936, P = 0.030). Moreover, no significant causal effect between SSc and BMR was observed in the reverse MR analysis (OR = 0.999, 95% CI: 0.997-1.001, P = 0.292). According to the sensitivity analysis, the presence of heterogeneity and genetic pleiotropy was not detected. Our findings, derived from a genetic perspective, provide robust evidence of a causal connection between BMR and SSc. To verify these results and clarify the potential mechanisms, further research is warranted.

UNASSIGNED: Systemic sclerosis (SSc) is a rare autoimmune disease with multiple organ involvement; however, the contribution of the nervous system (NS) remains relatively understudied. There are no specific data on the role of the autoimmune response and inflammation in the development of peripheral nerve system (PNS) damage in SSc and markers to assess this damage have yet to be identified.
UNASSIGNED: The primary objective of this study was to define the autoimmune mechanisms that lead to neuropathy by identifying antibodies (Abs) that target certain component of the NS or are associated with SSc. The secondary objective was to identify markers of NS damage that correlate with the detection and progression of polyneuropathy (PNP).
UNASSIGNED: This study included patients diagnosed with SSc who met ACR/EULAR 2013 classification criteria at two leading Latvian hospitals between January 2016 and December 2021. Patients underwent a nerve conduction study (NCS). The SSc-associated Abs, Abs against myelin-associated glycoprotein (MAG) and anti-ganglioside Abs (GM1, GM2, GD1a, GD1b and GQ1b) were analysed. Potential serum PNS biomarkers-neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), fibroblast growth factor 21 (FGF21) and growth/differentiation factor 15 (GDF15)-were measured.
UNASSIGNED: We recruited 103 Caucasian patients diagnosed with SSc. SSc-associated Abs did not differ significantly between patients with and without PNP (p > 0.05). Anti-MAG and anti-ganglioside Abs in patients with PNP did not present a significant increase above the reference range. NfL, GFAP and GDF15 were significantly elevated in the presence of PNP (p < 0.05), with a moderate to high effect size (r = 0.36-0.65). Our regression analysis revealed a strong association between the HAQ-DI score, older age, male gender and the risk of developing PNP.
UNASSIGNED: The development of PNP in patients with SSc is most likely due to ageing, natural progression and the sequelae of the disease. Several serum biomarkers-NfL, GFAP and GDF15-could be used as relevant diagnostic biomarkers for PNP in patients with SSc. Future studies are warranted to validate the diagnostic efficacy of these biomarkers and to unravel the complex interplay of factors leading to PNP in patients with SSc.

Endothelial cells (ECs) are widely distributed in the human body and play crucial roles in the circulatory and immune systems. ECs dysfunction contributes to the progression of various chronic cardiovascular, renal, and metabolic diseases. As a key transcription factor in ECs, FLI-1 is involved in the differentiation, migration, proliferation, angiogenesis and blood coagulation of ECs. Imbalanced FLI-1 expression in ECs can lead to various diseases. Low FLI-1 expression leads to systemic sclerosis by promoting fibrosis and vascular lesions, to pulmonary arterial hypertension by promoting a local inflammatory state and vascular lesions, and to tumour metastasis by promoting the EndMT process. High FLI-1 expression leads to lupus nephritis by promoting a local inflammatory state. Therefore, FLI-1 in ECs may be a good target for the treatment of the abovementioned diseases. This comprehensive review provides the first overview of FLI-1-mediated regulation of ECs processes, with a focus on its influence on the abovementioned diseases and existing FLI-1-targeted drugs. A better understanding of the role of FLI-1 in ECs may facilitate the design of more effective targeted therapies for clinical applications, particularly for tumour treatment.

OBJECTIVE: The characteristics of brain impairment in different subtypes of systemic sclerosis (SSc) (dcSSc, diffuse cutaneous SSc; lcSSc, limited cutaneous SSc) remain unclear. This study aimed to characterize cerebral structure and perfusion changes in different subtype of SSc patients using magnetic resonance (MR) imaging.
METHODS: Seventy SSc patients (46.0 ± 11.7 years, 62 females) and 30 healthy volunteers (44.8 ± 13.7 years, 24 females) were recruited and underwent brain MR imaging and Montreal Cognitive Assessment (MoCA) test. Gray matter (GM) volumes were measured using voxel-based morphometry analysis on T1-weighted images. Voxel-based and regional cerebral blood flow (CBF) was calculated on arterial spin labelling images. The cerebral structural and perfusion measurements by MR imaging were compared among dcSSc, lcSSc and healthy subjects using one-way ANOVA. The correlations between clinical characteristics and MR imaging measurements were also analyzed.
RESULTS: The dcSSc patients exhibited a significant reduction in GM volume in the para-hippocampal region (cluster p < 0.01, FWE corrected) compared with healthy volunteers. Whereas, SSc patients, particularly lcSSc patients, showed elevated CBF in cerebellum, insula, cerebral cortex, and subcortical structures (regional analyses: all p < 0.05; voxel-based analyses: cluster p < 0.01, FWE corrected). Furthermore, clinical characteristics of modified Rodnan skin score (mRSS) (r value ranged from -0.29 to -0.45), MoCA scores (r = 0.40) and antinuclear antibody (ANA) positivity (r=-0.33) were significantly associated with CBF in some regions (all p < 0.05).
CONCLUSIONS: The manifestations of brain involvement vary among different subtypes of SSc. In addition, severe skin sclerosis may indicate higher risk of brain involvement in SSc patients.

UNASSIGNED: Cellular and molecular biology, combined with research on the human microbiome and metabolome, have provided new insights into the pathogenesis of systemic sclerosis (SSc). However, most studies on gut microbiota (GM) and metabolome in SSc are observational studies. The impact of confounding factors and reverse causation leads to different insights. To shed light on this matter, we utilized Mendelian randomization (MR) to determine the causal effect of GM/metabolites on SSc.
UNASSIGNED: Based on summary-level data from genome-wide association studies, bidirectional Two-sample MR was conducted involving 196 GM, 1400 plasma metabolism, and 9,095 SSc. Inverse Variance Weighting (IVW) was mainly used for effect estimation.
UNASSIGNED: Forward MR analysis found that three GM and two plasma metabolites are causally related to SSc. IVW results showed Victivallaceae (family) (OR, 1.469; 95%CI, 1.099-1.963; p = 0.009) and LachnospiraceaeUCG004 (genus) (OR, 1.548; 95%CI, 1.020-2.349; p = 0.04) were risk factor of SSc. Conversely, Prevotella7 (genus) (OR, 0.759; 95%CI, 0.578-0.997; p = 0.048)was a protective factor of SSc. The results on plasma metabolites indicated that Pregnenediol disulfate (C21H34O8S2) levels (OR, 1.164; 95%CI, 1.006-1.347; p = 0.041)was a risk factor of SSc, while Sphingomyelin (d18:1/19:0, d19:1/18:0) levels (OR, 0.821; 95%CI, 0.677-0.996; p = 0.045)was a protective factor of SSc. Reverse MR analysis did not find causally relationship between SSc and the above GM/plasma metabolites.
UNASSIGNED: Our results revealed the causally effect between GM/plasma metabolites and SSc. These findings provided new insights into the mechanism of SSc. In particular, we demonstrated Prevotella7 was a protective factor of SSc despite its controversial role in SSc in previous researches.

B cells play a central role in the pathogenesis of systemic sclerosis (SSc). Most B-cell studies have focused on their pathological role as antibody producers. However, in addition to immunoglobulin secretion, these cells have a wide range of functions in the immune response, including antigen presentation to T cells and cytokine production. Importantly, not all B-cell subsets promote the immune response. Regulatory B cells (Bregs) attenuate inflammation and contribute to the maintenance of immune tolerance. However, effector B cells (Beffs) positively modulate the immune response through the production of various cytokines. In SSc, Bregs are insufficient and/or dysfunctional. B-cell-targeting biologics have been trialled with promising results in the treatment of SSc. These therapies can affect Bregs or Beffs, which can potentially limit their long-term efficacy. Future strategies might involve the modulation of effector B cells in combination with the stimulation of regulatory subsets. Additionally, the monitoring of individual B-cell subsets in patients may lead to the discovery of novel biomarkers that could help predict disease relapse or progression. The purpose of this review is to summarize the relevant literatures and explain how Bregs and Beffs jointly participate in the pathogenesis of SSc.

From sea shores to the abysses of the deep ocean, marine ecosystems have provided humanity with valuable medicinal resources. The use of marine organisms is discussed in ancient pharmacopoeias of different times and geographic regions and is still deeply rooted in traditional medicine. Thanks to present-day, large-scale bioprospecting and rigorous screening for bioactive metabolites, the ocean is coming back as an untapped resource of natural compounds with therapeutic potential. This renewed interest in marine drugs is propelled by a burgeoning research field investigating the molecular mechanisms by which newly identified compounds intervene in the pathophysiology of human diseases. Of great clinical relevance are molecules endowed with anti-inflammatory and immunomodulatory properties with emerging applications in the management of chronic inflammatory disorders, autoimmune diseases, and cancer. Here, we review the historical development of marine pharmacology in the Eastern and Western worlds and describe the status of marine drug discovery. Finally, we discuss the importance of conducting sustainable exploitation of marine resources through biotechnology.