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Journal of Translational Medicine Jun 2024Interstitial lung disease (ILD) is the primary cause of mortality in systemic sclerosis (SSc), an autoimmune disease characterized by tissue fibrosis. SSc-related ILD...
BACKGROUND
Interstitial lung disease (ILD) is the primary cause of mortality in systemic sclerosis (SSc), an autoimmune disease characterized by tissue fibrosis. SSc-related ILD (SSc-ILD) occurs more frequently in females aged 30-55 years, whereas idiopathic pulmonary fibrosis (IPF) is more prevalent in males aged 60-75 years. SSc-ILD occurs earlier than IPF and progresses rapidly. FCN1, FABP4, and SPP1 macrophages are involved in the pathogenesis of lung fibrosis; SPP1 macrophages demonstrate upregulated expression in both SSc-ILD and IPF. To identify the differences between SSc-ILD and IPF using single-cell analysis, clarify their distinct pathogeneses, and propose directions for prevention and treatment.
METHODS
We performed single-cell RNA sequencing on NCBI Gene Expression Omnibus (GEO) databases GSE159354 and GSE212109, and analyzed lung tissue samples across healthy controls, IPF, and SSc-ILD. The primary measures were the filtered genes integrated with batch correction and annotated cell types for distinguishing patients with SSc-ILD from healthy controls. We proposed an SSc-ILD pathogenesis using cell-cell interaction inferences, and predicted transcription factors regulating target genes using SCENIC. Drug target prediction of the TF gene was performed using Drug Bank Online.
RESULTS
A subset of macrophages activates the MAPK signaling pathway under oxidative stress. Owing to the lack of inhibitory feedback from ANNEXIN and the autoimmune characteristics, this leads to an earlier onset of lung fibrosis compared to IPF. During initial lung injury, fibroblasts begin to activate the IL6 pathway under the influence of SPP1 alveolar macrophages, but IL6 appears unrelated to other inflammatory and immune cells. This may explain why tocilizumab (an anti-IL6-receptor antibody) only preserves lung function in patients with early SSc-ILD. Finally, we identified BCLAF1 and NFE2L2 as influencers of MAPK activation in macrophages. Metformin downregulates NFE2L2 and could serve as a repurposed drug candidate.
CONCLUSIONS
SPP1 alveolar macrophages play a role in the profibrotic activity of IPF and SSc-ILD. However, SSc-ILD is influenced by autoimmunity and oxidative stress, leading to the continuous activation of MAPK in macrophages. This may result in an earlier onset of lung fibrosis than in IPF. Such differences could serve as potential research directions for early prevention and treatment.
Topics: Humans; Scleroderma, Systemic; Macrophages; Lung Diseases, Interstitial; Female; Male; Middle Aged; Adult; Idiopathic Pulmonary Fibrosis; Aged; Gene Expression Regulation; Single-Cell Analysis; Lung
PubMed: 38937794
DOI: 10.1186/s12967-024-05403-4 -
Journal of Psychosomatic Research Jun 2024Symptoms of anxiety increased early in the COVID-19 pandemic among people with systemic sclerosis (SSc) then returned to pre-pandemic levels, but this was an aggregate...
OBJECTIVE
Symptoms of anxiety increased early in the COVID-19 pandemic among people with systemic sclerosis (SSc) then returned to pre-pandemic levels, but this was an aggregate finding and did not evaluate whether vaccination may have contributed to reduced anxiety symptom levels. We investigated whether being vaccinated for COVID-19 was associated with reduced anxiety symptoms among people with SSc.
METHODS
The longitudinal Scleroderma Patient-centered Intervention Network (SPIN) COVID-19 Cohort was launched in April 2020 and included participants from the ongoing SPIN Cohort and external enrollees. Participants completed measures bi-weekly through July 2020, then every 4 weeks afterwards through August 2022 (32 assessments). We used linear mixed models to evaluate longitudinal trends of PROMIS Anxiety 4a v1.0 anxiety domain scores and their association with vaccination.
RESULTS
Among 517 participants included in analyses, 489 (95%) were vaccinated by September 2021, and no participants were vaccinated subsequently. Except for briefly at the beginning, when few had received a vaccine, and end, when only 28 participants remained unvaccinated, anxiety symptom trajectories were largely overlapping. Participants who were never vaccinated had higher anxiety symptoms by August 2022, but there were no other differences, and receiving a vaccination did not appear to change anxiety symptom trajectories meaningfully.
CONCLUSION
Vaccination did not appear to influence changes in anxiety symptoms among vulnerable people with SSc during the COVID-19 pandemic. This may be due to people restricting their behavior when they were unvaccinated and returning to more normal social engagement once vaccinated to maintain a steady level of anxiety symptoms.
PubMed: 38936011
DOI: 10.1016/j.jpsychores.2024.111852 -
Biomedicines Jun 2024This study aimed to clarify the association of HLA Class I and II with dcSSc and lcSSc in Thais. HLA typing for 11 gene loci (Class I: HLA-A, B and C, and Class II...
This study aimed to clarify the association of HLA Class I and II with dcSSc and lcSSc in Thais. HLA typing for 11 gene loci (Class I: HLA-A, B and C, and Class II [HLA-DR, DP and DQ]) was carried out using the Next Generation DNA Sequencing method (three fields) in 92 Thai patients with systemic sclerosis (55 dcSSc, 37 lcSSc) and 135 healthy controls (HCs). The distribution of HLA alleles in patients with dcSSc and lcSSc was compared. When compared with HCs, the AF of , , and showed an increasing trend in lcSSc patients without statistical significance. , , , , and increased significantly in dcSSc patients. and also increased significantly in lcSSc patients, but less significantly than in dcSSc patients. The association of with lcSSc was significantly protective. , and formed a three-locus haplotype that also constituted an eight-locus haplotype with , , , and . There was a possibility that HLA Class I would play a role in the pathogenesis of lcSSc, while Class II played more of a role in the dcSSc in Thai patients.
PubMed: 38927554
DOI: 10.3390/biomedicines12061347 -
Biomedicines Jun 2024In systemic sclerosis (SSc, or scleroderma), defective angiogenesis, clinically manifesting with abnormal capillary architecture and severe capillary reduction,... (Review)
Review
In systemic sclerosis (SSc, or scleroderma), defective angiogenesis, clinically manifesting with abnormal capillary architecture and severe capillary reduction, represents a hallmark of early-stage disease, usually preceding the onset of tissue fibrosis, and is caused by several cellular and molecular mechanisms affecting microvascular endothelial cells with different outcomes. Indeed, once damaged, endothelial cells can be dysfunctionally activated, thus becoming unable to undergo angiogenesis and promoting perivascular inflammation. They can also undergo apoptosis, transdifferentiate into profibrotic myofibroblasts, or acquire a senescence-associated secretory phenotype characterized by the release of exosomes and several profibrotic and proinflammatory mediators. In this narrative review, we aimed to give a comprehensive overview of recent studies dealing with the cellular and molecular mechanisms underlying SSc defective angiogenesis and the related endothelial cell dysfunctions, mainly the endothelial-to-mesenchymal transition process. We also discussed potential novel vascular treatment strategies able to restore the angiogenic process and reduce the endothelial-to-mesenchymal transition in this complex disease.
PubMed: 38927538
DOI: 10.3390/biomedicines12061331 -
Cureus May 2024Background and objective Morphea, or localized scleroderma (LS), is an autoimmune skin disorder characterized by inflammation and sclerosis. Its potential causes include...
Background and objective Morphea, or localized scleroderma (LS), is an autoimmune skin disorder characterized by inflammation and sclerosis. Its potential causes include infections, genetic predisposition, and trauma. The disease involves cycles of inflammation and fibrosis, leading to skin hardening and scarring, which can cause deformities if untreated. Research exploring the link between morphea and rheumatoid factor (RF), a marker associated with other autoimmune conditions, is ongoing. This study aimed to examine the less-explored role of RF, a marker typically linked to rheumatoid arthritis (RA), in the severity of morphea. It focused on assessing the levels of RF among morphea patients and its correlation with disease severity, intending to provide deeper insights into the condition and its management. Methods This study involved a simple randomized cross-sectional analysis to evaluate the role of the RF in measuring morphea severity among patients at the Dermatology and Venereology Department of Al-Sader Teaching Hospital from October 2022 to December 2023. We included participants with clinically and laboratory-confirmed morphea while excluding those with other autoimmune dermatological diseases, recent systemic steroid or immunosuppressive therapy, and pregnant women. The assessment of disease severity was done by utilizing the Localized Scleroderma Cutaneous Assessment Tool (LoSCAT). Statistical analyses were performed using SPSS Statistics version 27 (IBM Corp., Armonk, NY), with a significance threshold of p<0.05. Results Elevated RF levels were significantly associated with increased morphea severity, with severe cases showing higher RF levels (mean: 30.34 U/mL) compared to moderate (25.83 U/mL) and mild cases (21.56 U/mL) (p = 0.028). However, no significant correlation was found between RF levels and demographic factors such as age, gender, or occupation. Patients with high RF levels had a longer disease duration (mean: 57.15 years) compared to those with normal levels (25.83 years, p = 0.020). Significant differences were observed in lesion distribution on the back (p = 0.002). Logistic regression indicated that severe morphea patients were more likely to have elevated RF levels [odds ratio (OR): 1.158, p = 0.014]. Conclusions This study enriches our understanding of RF's role in morphea, revealing no significant correlation with demographic factors but suggesting its potential role in disease chronicity and severity.
PubMed: 38919251
DOI: 10.7759/cureus.61105 -
Arthritis Research & Therapy Jun 2024To determine the relationship between gastroesophageal reflux disease (GORD) and its treatment and interstitial lung disease in patients with systemic sclerosis (SSc).
BACKGROUND
To determine the relationship between gastroesophageal reflux disease (GORD) and its treatment and interstitial lung disease in patients with systemic sclerosis (SSc).
METHODS
SSc patients from the Australian Scleroderma Cohort Study (ASCS) were included. GORD was defined as self-reported GORD symptoms, therapy with a proton pump inhibitor (PPI) or histamine 2 receptor antagonist (H2RA) and/or the presence of reflux oesophagitis diagnosed endoscopically. The impact of GORD and its treatment on ILD features (including severity and time to ILD development) and survival was evaluated.
RESULTS
GORD was a common manifestation affecting 1539/1632 (94%) of SSc patients. GORD affected 450/469 (96%) of those with SSc-ILD cohort. In SSc-ILD, there was no relationship between the presence of GORD or its treatment and time to ILD development or ILD severity. However, GORD treatment was associated with improved survival in those with ILD (p = 0.002). Combination therapy with both a PPI and a H2RA was associated with a greater survival benefit than single agent therapy with PPI alone (HR 0.3 vs 0.5 p < 0.050 respectively).
CONCLUSION
GORD is a common SSc disease manifestation. While the presence or treatment of GORD does not influence the development or severity of ILD, aggressive GORD treatment, in particular with a combination of PPI and H2RA, is associated with improved survival in those with SSc-ILD.
Topics: Humans; Gastroesophageal Reflux; Lung Diseases, Interstitial; Female; Male; Middle Aged; Scleroderma, Systemic; Proton Pump Inhibitors; Aged; Histamine H2 Antagonists; Adult; Cohort Studies; Treatment Outcome; Australia
PubMed: 38918847
DOI: 10.1186/s13075-024-03355-0 -
BMC Rheumatology Jun 2024Systemic sclerosis (SSc) is a rare, complex autoimmune rheumatic disease with multiple factors that contribute to pain. People with SSc emphasize the effect pain has on...
Protocol for the development of a tool to map systemic sclerosis pain sources, patterns, and management experiences: a Scleroderma Patient-centered Intervention Network patient-researcher partnership.
INTRODUCTION
Systemic sclerosis (SSc) is a rare, complex autoimmune rheumatic disease with multiple factors that contribute to pain. People with SSc emphasize the effect pain has on their quality of life, but no studies have systematically examined the frequency and relative importance of different SSc pain sources, patterns of pain from different sources, and pain management experiences. Our objectives are to (1) develop a tool, jointly with researchers, health care providers, and patients, to map sources of pain in SSc, determine patterns of pain from different sources, and understand pain management experiences; and (2) administer the final tool version to participants in the large multinational Scleroderma Patient-centered Intervention Network (SPIN) Cohort.
METHODS
First, we will use validated pain assessment tools as templates to develop an initial version of our pain assessment tool, and we will obtain input from patient advisors to adapt it for SSc. The tool will include questions on pain sources, pain patterns, pain intensity, pain management techniques, and barriers to pain management in SSc. Second, we will conduct nominal group technique sessions with people living with SSc and health care providers who care for people with SSc to further refine the tool. Third, we will conduct individual usability testing sessions with SPIN Cohort participants. Once the tool has been finalized, we will administer it to individuals in the multinational SPIN Cohort, which currently includes over 1,300 active participants from 54 sites in 7 countries. We will perform unsupervised clustering using the KAy-Means for MIxed LArge data (KAMILA) method to identify participant subgroups with similar profiles of pain sources (present or absent) and to evaluate predictors of subgroup membership. We will use latent profile analysis to identify subgroups of participants with similar profiles based on pain intensity scores for each pain source and evaluate predictors.
DISCUSSION
Once completed, our pain assessment tool will allow our team and other researchers to map sources of pain in SSc and to understand pain management experiences of people living with SSc. This knowledge will provide avenues for studies on the pathophysiology of pain in SSc and studies of interventions to improve pain management.
PubMed: 38907303
DOI: 10.1186/s41927-024-00398-3 -
Scientific Reports Jun 2024Primary biliary cholangitis (PBC) is frequently associated with autoimmune disease. Although PBC complicated with CREST syndrome (PBC-CREST) has been reported, the...
Primary biliary cholangitis (PBC) is frequently associated with autoimmune disease. Although PBC complicated with CREST syndrome (PBC-CREST) has been reported, the long-term outcomes of the affected patients have not been fully investigated. Herein, the long-term outcomes of PBC-CREST were evaluated. Next, the GLOBE and UK-PBC scores were validated and compared between the PBC alone and PBC-CREST groups. A total of 302 patients who were diagnosed with PBC between December 1990 and August 2021 at Fukushima Medical University Hospital were included. The liver transplantation (LT)-free survival rates were compared between patients with PBC alone (n = 245) and those with PBC-CREST (n = 57). Moreover, 173 patients, excluding those with liver-related death/LT within 1 year after ursodeoxycholic acid administration, were divided into two subgroups (PBC alone (n = 147) and PBC-CREST (n = 26)), and the GLOBE and UK-PBC scores were compared between the subgroups. The survival rates without LT (3/5/10 years) were 92/87/80% for the PBC-alone group and 98/96/96% for the PBC-CREST group, with a significantly better prognosis in the PBC-CREST group (log-rank P = 0.0172). Multivariate analysis revealed that the presence of CREST syndrome is an independent protective factor for the presence of cirrhosis. The predicted 5/10/15-year risks of liver-related death or LT based on the UK-PBC score were significantly lower in the PBC-CREST group (2.4/7.6/13.2%) than in the PBC-alone group (4.8/11.8/18.8%) (P < 0.05). The predicted 3/5-year LT-free survival rates based on the GLOBE score were significantly higher in the PBC-CREST group (93/88%) than in the PBC-alone group (88/81%) (P < 0.05). Patients with PBC-CREST may have better long-term outcomes than those with PBC alone.
Topics: Humans; Female; Male; Liver Cirrhosis, Biliary; Middle Aged; Aged; Liver Transplantation; CREST Syndrome; Prognosis; Adult; Survival Rate; Retrospective Studies
PubMed: 38898064
DOI: 10.1038/s41598-024-64976-8 -
Journal of Clinical Medicine May 2024Depressive disorders are a growing problem worldwide. They are also characterized by high comorbidity, including from the circle of dermatological diseases. Autoimmune... (Review)
Review
Depressive disorders are a growing problem worldwide. They are also characterized by high comorbidity, including from the circle of dermatological diseases. Autoimmune diseases seem to be particularly correlated with depressive comorbidity, raising the question of their possible common pathomechanism. The PubMed database was searched, focusing on results published after 2016. A particular reciprocal correlation of depressive disorders with psoriasis, atopic dermatitis, alopecia areata, impetigo, lupus and systemic scleroderma was found. One possible explanation for the co-occurrence of the above diseases is that the inflammatory theory may be applicable to depression, the various elements of which also apply to autoimmune diseases.
PubMed: 38892934
DOI: 10.3390/jcm13113224 -
Journal of Clinical Medicine May 2024Systemic sclerosis (SSc) represents a rare and intricate autoimmune connective tissue disease, the pathophysiology of which has not been fully understood. Its key... (Review)
Review
Systemic sclerosis (SSc) represents a rare and intricate autoimmune connective tissue disease, the pathophysiology of which has not been fully understood. Its key features include progressive fibrosis of the skin and internal organs, vasculopathy and aberrant immune activation. While various anti-nuclear antibodies can serve as biomarkers for the classification and prognosis of SSc, their direct role in organ dysfunction remains unclear. Anti-Th/To antibodies are present in approximately 5% of SSc patients, and are particularly prevalent among those with the limited subtype of the disease. Although the presence of these autoantibodies is associated with a mild course of the disease, there is a strong connection between them and severe clinical manifestations of SSc, including interstitial lung disease, pulmonary arterial hypertension and gastrointestinal involvement. Also, the additional clinical correlations, particularly with malignancies, need further research. Moreover, the disease's course seems to be influenced by antibodies, specific serum cytokines and TLR signaling pathways. Understanding the relationships between presence of anti-Th/To, its molecular aspects and response to treatment options is crucial for the development of novel, personalized therapeutic techniques and should undergo profound analysis in future studies.
PubMed: 38892733
DOI: 10.3390/jcm13113022