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Annals of the Rheumatic Diseases Dec 2023The severity of skin involvement in diffuse cutaneous systemic sclerosis (dcSSc) depends on stage of disease and differs between anti-RNA-polymerase III (ARA) and...
OBJECTIVES
The severity of skin involvement in diffuse cutaneous systemic sclerosis (dcSSc) depends on stage of disease and differs between anti-RNA-polymerase III (ARA) and anti-topoisomerase antibody (ATA) subsets. We have investigated cellular differences in well-characterised dcSSc patients compared with healthy controls (HCs).
METHODS
We performed single-cell RNA sequencing on 4 mm skin biopsy samples from 12 patients with dcSSc and HCs (n=3) using droplet-based sequencing (10× genomics). Patients were well characterised by stage (>5 or <5 years disease duration) and autoantibody (ATA+ or ARA+). Analysis of whole skin cell subsets and fibroblast subpopulations across stage and ANA subgroup were used to interpret potential cellular differences anchored by these subgroups.
RESULTS
Fifteen forearm skin biopsies were analysed. There was a clear separation of SSc samples, by disease, stage and antibody, for all cells and fibroblast subclusters. Further analysis revealed differing cell cluster gene expression profiles between ATA+ and ARA+ patients. Cell-to-cell interaction suggest differing interactions between early and late stages of disease and autoantibody. TGFβ response was mainly seen in fibroblasts and smooth muscle cells in early ATA+dcSSc skin samples, whereas in early ARA+dcSSc patient skin samples, the responding cells were endothelial, reflect broader differences between clinical phenotypes and distinct skin score trajectories across autoantibody subgroups of dcSSc.
CONCLUSIONS
We have identified cellular differences between the two main autoantibody subsets in dcSSc (ARA+ and ATA+). These differences reinforce the importance of considering autoantibody and stage of disease in management and trial design in SSc.
Topics: Humans; Autoantibodies; Scleroderma, Systemic; Scleroderma, Diffuse; Skin; Single-Cell Analysis
PubMed: 37580109
DOI: 10.1136/ard-2023-224184 -
Reumatologia Clinica Oct 2023Keloidal or nodular scleroderma (NS) is a variant of localized scleroderma (LS) frequently seen in patients with limited or diffuse systemic sclerosis (SSc). It presents...
Keloidal or nodular scleroderma (NS) is a variant of localized scleroderma (LS) frequently seen in patients with limited or diffuse systemic sclerosis (SSc). It presents as raised, firm plaques or nodules with extensive dermal fibrosis and hyalinized collagen bundles. We present a patient with SSc who presented with this rare entity.
Topics: Humans; Scleroderma, Localized; Scleroderma, Systemic; Keloid
PubMed: 37805259
DOI: 10.1016/j.reumae.2023.02.009 -
Laryngoscope Investigative... Dec 2023Scleroderma is a complex chronic progressive immune-mediated disease that causes fibrosis of the skin and internal organs, and vasculopathy.Ear involvement has been...
OBJECTIVE
Scleroderma is a complex chronic progressive immune-mediated disease that causes fibrosis of the skin and internal organs, and vasculopathy.Ear involvement has been poorly studied in patients with scleroderma. Vasculitic and autoimmune mechanisms are considered as possible etiologies on hearing impairment, however, this etiology still unclear.Herein, we reviewed three cases of scleroderma from a temporal bone repository.
METHODS
The national temporal bone database was reviewed for cases with scleroderma. Clinical case review and correlative otopathologic analysis. Middle and inner ear otopathologic analysis was performed following hematoxylin and eosin staining under light microscopy. Findings were compared to three age-matched controls.
RESULTS
Two patients (three cases) with a history of serologically confirmed scleroderma were identified. Both individuals reported tinnitus and demonstrated bilateral moderate to severe down-sloping sensorineural hearing loss on audiometry. Histologically, the incudomallear joint space was diminished and ossicles appeared demineralized. A loss of hyaline cartilage, and obliteration of the incudomallear and incudostapedial joint synovial spaces was observed. Decreased caliber and intimal hyperplasia of arteries adjacent to ossicles was also identified. Mild diffuse atrophy of stria vascularis in the middle and apical turns of cochlea were found. Hair cell populations were normal. Total spiral ganglion neurons were lower in cases of scleroderma (range 29%-51%) compared to age-matched controls.
CONCLUSION
Fibrosis, inflammation, and vascular changes were observed in the middle and inner ear in patients with scleroderma. Findings have implications for understanding hearing and vestibular dysfunction in this patient population.
LEVEL OF EVIDENCE
Retrospective study.
PubMed: 38130272
DOI: 10.1002/lio2.1180 -
International Journal of Molecular... Jun 2023This study investigated the role of IL-35 in systemic sclerosis (SSc) patients, focusing on CD4+ T cell response and immunomodulatory cytokine production. By comparing...
This study investigated the role of IL-35 in systemic sclerosis (SSc) patients, focusing on CD4+ T cell response and immunomodulatory cytokine production. By comparing the cytokine levels in healthy donors (HD) and SSc patients using ELISAs, we found a significantly lower plasma IL-35 concentration in the SSc patients (52.1 ± 5.6 vs. 143 ± 11.1, < 0.001). Notably, the IL-35 levels showed a negative correlation with TGF-β ( < 0.001) and IL-17 ( = 0.04). Assessing the IL-35R expression across cell types in the SSc patients and HDs via flow cytometry, we found higher levels on monocytes (40.7 + 5.7 vs. 20.3 ± 1.9, < 0.001) and lower levels on CD8+ T cells (61.8 ± 9.2 vs. 83.4 ± 0.8, < 0.05) in the SSc patients. The addition of recombinant IL-35 to stimulated peripheral blood mononuclear cells reduced the IL-17+CD4+ T cell percentage (9.0 ± 1.5 vs. 4.8 ± 0.7, < 0.05) and increased the IL-35+CD4+ T percentage (4.1 ± 2.3 vs. 10.2 ± 0.8, < 0.001). In a Treg:Tresponder cell Sco-culture assay with HD and SSc samples, rIL35 decreased the cell proliferation and levels of IL-17A (178.2 ± 30.5 pg/mL vs. 37.4 ± 6.4 pg/mL, < 0.001) and TGF-β (4194 ± 777 pg/mL vs. 2413 ± 608 pg/mL, < 0.01). Furthermore, we observed a positive correlation between the modified Rodnan skin score (mRSS) and TGF-β ( < 0.001), while there was a negative correlation between mRSS and IL-35 ( = 0.004). Interestingly, higher levels of plasmatic IL-35 were detected in individuals with limited disease compared to those with diffuse disease (60.1 ± 8.0 vs. 832.3 ± 4.1, < 0.05). These findings suggest that IL-35 exhibits anti-inflammatory properties in SSc and it may serve as a marker for disease severity and a therapeutic target.
Topics: Humans; Interleukin-17; Leukocytes, Mononuclear; Scleroderma, Systemic; Cytokines; Transforming Growth Factor beta
PubMed: 37445745
DOI: 10.3390/ijms241310567 -
Journal of Cardiology Aug 2023Systemic sclerosis (SSc) is divided into diffuse and limited cutaneous SSc (dcSSc and lcSSc). The dcSSc subtype has more severe internal organ damage. This study aimed...
BACKGROUND
Systemic sclerosis (SSc) is divided into diffuse and limited cutaneous SSc (dcSSc and lcSSc). The dcSSc subtype has more severe internal organ damage. This study aimed to assess whether cardiovascular magnetic resonance (CMR) parametric mapping could detect early cardiac involvement and evaluate differences between these two subtypes.
METHODS
Eighty SSc patients (37 dcSSc and 43 lcSSc) underwent CMR at 3.0 T (Philips Healthcare, Best, The Netherlands) in our hospital between July 2018 and July 2021. We analyzed myocardial damage by CMR parametric mapping and compared it with clinical data.
RESULTS
The median duration of the disease was 10.2 months. The left ventricular ejection fraction was preserved in both groups. DcSSc had significantly higher native T1 (1333.4 ± 71.2 ms vs. 1295.0 ± 42.7 ms, p = 0.006) and extracellular volume fraction (32.6 ± 4.1 % vs. 30.3 ± 4.0 %, p = 0.018) in the mid-ventricular septum as compared to lcSSc, although there were no differences in T2 values. Native T1 values were positively correlated with the E/e' ratio and left atrial volume indices evaluated by transthoracic echocardiography in overall SSc and dcSSc, but not in lcSSc. Logistic regression analysis revealed that native T1 was an independent predictor of left ventricular diastolic dysfunction in SSc patients (odds ratio, 1.194; 95 % confidence interval, 1.021-1.396; p = 0.026). Native T1 was higher in SSc patients with progressive skin lesions. Additionally, there were positive correlations between brain natriuretic peptide, New York Heart Association functional classification, and native T1.
CONCLUSIONS
CMR parametric mapping is a useful tool for detecting myocardial changes. Native T1 was the most sensitive parameter for identifying diffuse myocardial changes in the early stages of SSc and was associated with left ventricular diastolic function. DcSSc had more severe myocardial involvement than lcSSc; therefore, the use of CMR parametric mapping may aid in its prediction.
Topics: Humans; Stroke Volume; Ventricular Function, Left; Scleroderma, Systemic; Myocardium; Heart
PubMed: 36921691
DOI: 10.1016/j.jjcc.2023.03.003 -
European Journal of Translational... Feb 2024We aimed to investigate sleep disorders in patients with systemic scleroderma (SSc) and its relationship with socio-demographic and medical factors and to provide a...
We aimed to investigate sleep disorders in patients with systemic scleroderma (SSc) and its relationship with socio-demographic and medical factors and to provide a suitable solution to better control the disease and improve the quality of life in these patients. This cross-sectional study evaluated SSc patients seen at a rheumatology clinic from September 1, 2022, through April 1, 2023.The patients were examined by the main investigator of the project and entered the study after taking the medical history and meeting the criteria of ACR 2013 Classification Criteria. Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS) and STOP-Bang Questionnaire were employed to investigate sleep disorders. A total of 103 patients were included in the study. The average age of the patients was 48.42 ± 12.4 years. PSQI showed lower quality of sleep scores among SSc (68% of patients), which was significantly related to the degree of skin stiffness in patients, telangiectasia, interstitial lung disease (ILD) in computed tomography (CT) scan, patient age, duration of the disease, and pulmonary artery pressure (PAP). STOP-Bang Questionnaire revealed that obstructive sleep apnea (OSA) was significantly associated with telangiectasia, ILD, patient age, disease onset age, disease duration, body mass index and PAP. Insomnia had a statistically significant relationship with telangiectasia, ILD and patient age. Drowsiness during daily activities was not significantly related to any of the individual variables and disease-related variables. Sleep disorders are common in patients with systemic scleroderma. Telangiectasia, ILD and patient age were related to all sleep quality disorders and respiratory apnea and insomnia. Furthermore, the amount of skin involvement significantly causes disturbances in the quality of sleep of patients, where in the group with diffuse skin stiffness, 80% of patients exhibited disturbances in the quality of sleep. Therefore, paying attention to sleep health can be an effective factor in improving the quality of life of patients with SSc.
PubMed: 38351839
DOI: 10.4081/ejtm.2024.12183 -
EClinicalMedicine Aug 2023Systemic sclerosis is a heterogenous disease in which little is known about patterns of patient-reported symptom clusters. We aimed to identify classes of individuals...
Patterns of patient-reported symptoms and association with sociodemographic and systemic sclerosis disease characteristics: a scleroderma Patient-centered Intervention Network (SPIN) Cohort cross-sectional study.
BACKGROUND
Systemic sclerosis is a heterogenous disease in which little is known about patterns of patient-reported symptom clusters. We aimed to identify classes of individuals with similar anxiety, depression, fatigue, sleep disturbance, and pain symptoms and to evaluate associated sociodemographic and disease-related characteristics.
METHODS
This multi-centre cross-sectional study used baseline data from Scleroderma Patient-centered Intervention Network Cohort participants enrolled from 2014 to 2020. Eligible participants completed the PROMIS-29 v2.0 measure. Latent profile analysis was used to identify homogeneous classes of participants based on patterns of anxiety, depression, fatigue, sleep disturbance, and pain scores. Sociodemographic and disease-related characteristics were compared across classes.
FINDINGS
Among 2212 participants, we identified five classes, including four classes with "Low" (565 participants, 26%), "Normal" (651 participants, 29%), "High" (569 participants, 26%), or "Very High" (193 participants, 9%) symptom levels across all symptoms. Participants in a fifth class, "High Fatigue/Sleep/Pain and Low Anxiety/Depression" (234 participants, 11%) had similar levels of fatigue, sleep disturbance, and pain as in the "High" class but low anxiety and depression symptoms. There were significant and substantive trends in sociodemographic characteristics (age, education, race or ethnicity, marital or partner status) and increasing disease severity (diffuse disease, tendon friction rubs, joint contractures, gastrointestinal symptoms) across severity-based classes. Disease severity and sociodemographic characteristics of "High Fatigue/Sleep/Pain and Low Anxiety/Depression" class participants were similar to the "High" severity class.
INTERPRETATION
Most people with systemic sclerosis can be classified by levels of patient-reported symptoms, which are consistent across symptoms and highly associated with sociodemographic and disease-related variables, except for one group which reports low mental health symptoms despite high levels of other symptoms and substantial disease burden. Studies are needed to better understand resilience in systemic sclerosis and to identify and facilitate implementation of cognitive and behavioural strategies to improve coping and overall quality of life.
FUNDING
National Institute of Nursing Research (F31NR019007), Canadian Institutes of Health Research, Arthritis Society Canada, the Lady Davis Institute for Medical Research, the Jewish General Hospital Foundation, McGill University, Scleroderma Society of Ontario, Scleroderma Canada, Sclérodermie Québec, Scleroderma Manitoba, Scleroderma Atlantic, Scleroderma Association of BC, Scleroderma SASK, Scleroderma Australia, Scleroderma New South Wales, Scleroderma Victoria, and Scleroderma Queensland.
PubMed: 37533421
DOI: 10.1016/j.eclinm.2023.102104 -
Arthritis Research & Therapy Sep 2023Interstitial lung disease (ILD) is the most common cause of death in patients with systemic sclerosis (SSc). Prognostic biomarkers are needed to identify SSc-ILD...
BACKGROUND
Interstitial lung disease (ILD) is the most common cause of death in patients with systemic sclerosis (SSc). Prognostic biomarkers are needed to identify SSc-ILD patients at risk for progressive pulmonary fibrosis. This study investigates autoantibodies measured in bronchoalveolar lavage (BAL) fluid and in serum in reference to the clinical disease course of SSc-ILD.
METHODS
Fifteen patients with new onset SSc-ILD underwent bronchoscopy. Autoantibody levels were analyzed using addressable laser bead immunoassay from BAL fluid and the serum. In a separate longitudinal cohort of 43 patients with early SSc-ILD, autoantibodies in serum were measured at baseline and pulmonary function tests were performed at least 2 times over the course of at least 2 or more years. Linear mixed effect models were created to investigate the relationship between specific autoantibodies and progression of SSc-ILD. Finally, lung tissue from healthy controls and from subjects with SSc was analyzed for the presence of the Ro52 antigen using immunohistochemistry.
RESULTS
Among SSc-ILD patients who were positive for anti-Ro52 (N = 5), 3 (60%) had enrichment of anti-Ro52 in BAL fluid at a ratio exceeding 50x. In the longitudinal cohort, 10/43 patients (23%) were anti-Ro52 positive and 16/43 (37%) were anti-scl-70 positive. Presence of anti-Scl-70 was associated with a lower vital capacity (VC) at baseline (-12.6% predicted VC [%pVC]; 95%CI: -25.0, -0.29; p = 0.045), but was not significantly associated with loss of lung function over time (-1.07%pVC/year; 95%CI: -2.86, 0.71; p = 0.230). The presence of anti-Ro52 was significantly associated with the loss of lung function over time (-2.41%pVC/year; 95% CI: -4.28, -0.54; p = 0.013). Rate of loss of lung function increased linearly with increasing anti-Ro52 antibody levels (-0.03%pVC per arbitrary units/mL and year; 95%CI: -0.05, -0.02; p < 0.001). Immunohistochemical staining localized the Ro52 antigen to alveolar M2 macrophages in peripheral lung tissue both in subjects with and without SSc.
CONCLUSIONS
This study suggests that antibodies targeting Ro52 are enriched in the lungs of patients with new-onset SSc-ILD, linking Ro52 autoimmunity to the pulmonary pathology of SSc. Clinical and immunohistochemical data corroborates these findings and suggest that anti-Ro52 may serve as a potential biomarker of progressive SSc-ILD.
Topics: Humans; Lung Diseases, Interstitial; Scleroderma, Systemic; Autoantibodies; Pulmonary Fibrosis; Scleroderma, Diffuse
PubMed: 37667402
DOI: 10.1186/s13075-023-03141-4