| 1. |
- Morrisroe, Kathleen, et al.
(författare)
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Determinants of health-related quality of life in a multinational systemic sclerosis inception cohort
- 2018
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Ingår i: Clinical and Experimental Rheumatology. - 0392-856X. ; 36:4, s. 53-60
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: To evaluate health-related quality of life (HRQoL) and its determinants in a systemic sclerosis (SSc) multinational inception cohort. We performed a meta-analysis of data from individual countries, and compared the meta-analysis to individual country results by pooling data from each of the countries.METHODS: SSc patients within 2 years of disease onset were recruited from 5 countries participating in the International Systemic Sclerosis Inception Cohort (INSYNC). Data from each country's database were exported for analysis using a harmonised platform. HRQoL was assessed using the Medical Outcomes Short Form-36 (SF-36). Multivariate linear regression assessed associations between HRQoL and predictors in cohorts separately and meta-analyzed to generate pooled estimates. The analyses were repeated using individual patient data.RESULTS: Of the 637 SSc patients recruited, the majority was female (80.2%-83.3%), aged between 52.4-56.7 years with limited cutaneous disease subtype (48.6%-66.7%). HRQoL scores were lower for SSc patients than the general population (SF-36 physical component summary (PCS) score (36.4-39.6), mental component summary (MCS) score (41.0-46.4)). Determinants of SF-36 PCS by meta-analysis included increasing age (β=-0.1, 95%CI -0.2, -0.01), diffuse cutaneous disease subtype (β=-8.4, 95%CI -10.6, -6.3), and pulmonary arterial hypertension (β=-10.9, 95%CI -16.6, -5.3). Increasing age (β=0.09, 95%CI 0.0, 0.18) was the only variable associated with SF-36 MCS. Analyses using individual patient data revealed similar results to those of the meta-analysis of cohort data.CONCLUSIONS: Our study provides estimates of HRQoL in a large inception SSc cohort and provides evidence that individual patient data analysis is valid in the INSYNC dataset.
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| 2. |
- Spierings, Julia, et al.
(författare)
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A randomised, open-label trial to assess the optimal treatment strategy in early diffuse cutaneous systemic sclerosis : The UPSIDE study protocol
- 2021
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 11:3
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Tidskriftsartikel (refereegranskat)abstract
- Introduction Systemic sclerosis (SSc) is a chronic, autoimmune connective tissue disease associated with high morbidity and mortality, especially in diffuse cutaneous SSc (dcSSc). Currently, there are several treatments available in early dcSSc that aim to change the disease course, including immunosuppressive agents and autologous haematopoietic stem cell transplantation (HSCT). HSCT has been adopted in international guidelines and is offered in current clinical care. However, optimal timing and patient selection for HSCT are still unclear. In particular, it is unclear whether HSCT should be positioned as upfront therapy or rescue treatment for patients refractory to immunosuppressive therapy. We hypothesise that upfront HSCT is superior and results in lower toxicity and lower long-term medical costs. Therefore, we propose this randomised trial aiming to determine the optimal treatment strategy for early dcSSc by comparing two strategies used in standard care: (1) upfront autologous HSCT versus (2) immunosuppressive therapy (intravenous cyclophosphamide pulse therapy followed by mycophenolate mofetil) with rescue HSCT in case of treatment failure. Methods and analysis The UPSIDE (UPfront autologous hematopoietic Stem cell transplantation vs Immunosuppressive medication in early DiffusE cutaneous systemic sclerosis) study is a multicentre, randomised, open-label, controlled trial. In total, 120 patients with early dcSSc will be randomised. The primary outcome is event-free survival at 2 years after randomisation. Secondary outcomes include serious adverse events, functional status and health-related quality of life. We will also evaluate changes in nailfold capillaroscopy pattern, pulmonary function, cardiac MR and high-resolution CT of the chest. Follow-up visits will be scheduled 3-monthly for 2 years and annually in the following 3 years. Ethics and dissemination The study was approved by the Dutch Central Committee on Research Concerning Human Subjects (NL72607.041.20). The results will be disseminated through patient associations and conventional scientific channels. Trial registration numbers NCT04464434; NL 8720.
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| 3. |
- van Bon, L., et al.
(författare)
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Distinct evolution of TLR-mediated dendritic cell cytokine secretion in patients with limited and diffuse cutaneous systemic sclerosis
- 2010
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 1468-2060 .- 0003-4967. ; 69:8, s. 1539-1547
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Tidskriftsartikel (refereegranskat)abstract
- Background Systemic sclerosis (SSc) is an autoimmune disease and accumulating evidence suggests a role for Toll-like receptor (TLR)-mediated activation of dendritic cells (DCs). Objective To map TLR-mediated cytokine responses of DCs from patients with SSc. Methods 45 patients with SSc were included. Patients were stratified as having diffuse cutaneous SSc (dSSc) or limited cutaneous SSc (lSSc) according to the extent of skin involvement, and further divided into those with late (> 3 years) or early disease (< 2 years). DCs were stimulated with ligands for TLR2, TLR3, TLR4, TLR7/8 or combinations. Plasma samples were collected from patients with SSc (n = 167) and measured for interleukin 6 (IL-6), tumour necrosis factor a (TNF alpha), IL-12, IL-10 and interferon gamma. Results Stimulation of DC subsets from patients with early lSSc and dSSc with ligands for TLR2, TLR3 or TLR4 resulted in higher secretion of IL-6 and TNF alpha compared with those having late disease or healthy controls. Remarkably, the production of IL-12 was lower upon stimulation with TLR ligands in most patients with SSc, whereas the secretion of IL-10 was very high in patients with the dSSc phenotype, particularly in those having early dSSc. The combination of various TLR ligands led to reduced cytokine secretion in all patients with SSc. Circulating levels of these cytokines further underscored the presence of differences between various SSc phenotypes. Discussion The altered TLR-mediated activation of DCs may be responsible for Th2 skewed T-cell activation in SSc that may be orchestrated by fibrogenic T-cell cytokines, such as IL-4 and IL-13. DC targeting could thus offer new avenues for therapeutic intervention.
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| 4. |
- Andréasson, Kristofer, et al.
(författare)
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Mycophenolate mofetil for systemic sclerosis : drug exposure exhibits considerable inter-individual variation-a prospective, observational study
- 2020
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Ingår i: Arthritis Research & Therapy. - : BMC. - 1478-6362 .- 1478-6354. ; 22
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Mycophenolate mofetil (MMF) is an established therapy for systemic sclerosis (SSc), but its pharmacokinetics in this disease remains unexplored. We have investigated drug exposure in MMF-treated patients with SSc in relation to clinical features of the disease and common concomitant drugs.Methods: This study was predefined to include 35 MMF-treated SSc patients who were using MMF at a fixed dose of 0.5, 1.0 or 1.5g twice daily since at least 3months. The 12-h drug exposure of the active MMF metabolite mycophenolic acid (MPA) was estimated by repeated analysis of plasma MPA over a 6-h period. This 12-h drug exposure was dose normalised to a daily intake of 3g MMF (MPA_AUC(3g)) in order to compare subjects using MMF at different doses. Drug exposure was analysed in reference to the clinical characteristics including body weight, renal function, autoantibodies, intestinal dysbiosis, intestinal inflammation assessed by faecal (F)-calprotectin, intestinal symptoms assessed by the University of California Los Angeles Scleroderma Trial Consortium Gastrointestinal Tract Instrument 2.0 and concomitant drug usage including proton-pump inhibitors (PPI).Results:Thirty-four out of 35 study participants completed the study. The mean daily MMF dose was 2.1g. Drug exposure expressed as MPA_AUC(3g) varied up to 8-fold between patients (median 115, range 27-226mg h/L).MPA_AUC(3g) was inversely related to body weight (r(s)=-0.58, p<0.001) and renal function (r(s)=-0.34, p=0.054). Anti-topoisomerase-1 antibodies and male sex were associated with lower MPA_AUC(3g) (87 vs 123 and 71 vs 141; p=0.008 and p=0.015, respectively). MPA_AUC(3g) was inversely related to the intestinal abundance of lactobacilli and to F-calprotectin (r(s)=-0.54, p=0.004; r(s)=-0.36, p=0.034), but not to gastrointestinal symptoms. MPA_AUC(3g) was inversely related to PPI usage (r(s)=-0.45, p=0.007). We found no association between MPA_AUC(3g) and disease subtype, disease duration or disease activity.Conclusion: MMF-treated SSc patients exhibit considerable inter-individual variation in drug exposure, and lower MPA levels were primarily found in PPI users with poor prognostic factors. Body weight, renal function, sex, serology, gastrointestinal manifestations and/or measuring individual MPA exposure should be considered when using MMF for SSc.
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| 5. |
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| 6. |
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| 7. |
- Bengtsson, Anders A., et al.
(författare)
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Metabolic Profiling of Systemic Lupus Erythematosus and Comparison with Primary Sjögren’s Syndrome and Systemic Sclerosis
- 2016
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:7
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Tidskriftsartikel (refereegranskat)abstract
- Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease which can affect most organ systems including skin, joints and the kidney. Clinically, SLE is a heterogeneous disease and shares features of several other rheumatic diseases, in particular primary Sjögrens syndrome (pSS) and systemic sclerosis (SSc), why it is difficult to diag- nose The pathogenesis of SLE is not completely understood, partly due to the heterogeneity of the disease. This study demonstrates that metabolomics can be used as a tool for improved diagnosis of SLE compared to other similar autoimmune diseases. We observed differences in metabolic profiles with a classification specificity above 67% in the comparison of SLE with pSS, SSc and a matched group of healthy individuals. Selected metabolites were also significantly different between studied diseases. Biochemical pathway analysis was conducted to gain understanding of underlying pathways involved in the SLE pathogenesis. We found an increased oxidative activity in SLE, supported by increased xanthine oxidase activity and an increased turnover in the urea cycle. The most discriminatory metabolite observed was tryptophan, with decreased levels in SLE patients compared to control groups. Changes of tryptophan levels were related to changes in the activity of the aromatic amino acid decarboxylase (AADC) and/or to activation of the kynurenine pathway.
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| 8. |
- Broen, Jasper C A, et al.
(författare)
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The Functional Polymorphism 844 A>G in Fc{alpha}RI (CD89) Does Not Contribute to Systemic Sclerosis or Rheumatoid Arthritis Susceptibility.
- 2011
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 38:3, s. 446-449
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the role of the Fc(α)RI 844 A>G functional polymorphism in the genetic predisposition to rheumatoid arthritis (RA) and systemic sclerosis (SSc) susceptibility. METHODS: The study population was composed of 1401 patients with SSc, 642 patients with RA, and 1317 healthy controls. The Fc(α)RI (CD89) single-nucleotide polymorphism rs16986050 was genotyped by pyrosequencing. RESULTS: We observed no significant deviation of the genotype and allele frequencies in RA and SSc compared to controls. A metaanalysis and a recessive and dominant model yielded similar negative results. CONCLUSION: Our data show that the Fc(α)RI 844 A>G polymorphism is not associated with SSc or RA susceptibility.
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| 9. |
- Gyllenhammar, Tom, et al.
(författare)
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Decreased global myocardial perfusion at adenosine stress as a potential new biomarker for microvascular disease in systemic sclerosis : A magnetic resonance study
- 2018
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Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Patients with systemic sclerosis (SSc) have high cardiovascular mortality even though there is no or little increase in prevalence of epicardial coronary stenosis. First-pass perfusion on cardiovascular magnetic resonance (CMR) have detected perfusion defects indicative of microvascular disease, but the quantitative extent of hypoperfusion is not known. Therefore, we aimed to determine if patients with SSc have lower global myocardial perfusion (MP) at rest or during adenosine stress, compared to healthy controls, quantified with CMR. Methods: Nineteen SSc patients (17 females, 61 ± 10 years) and 22 controls (10 females, 62 ± 11 years) underwent CMR. Twelve patients had limited cutaneous SSc and 7 patients had diffuse cutaneous SSc. One patient had pulmonary arterial hypertension (PAH). MP was quantified using coronary sinus flow (CSF) measurements at rest and during adenosine stress, divided by left ventricular mass (LVM). Results: There was no difference in MP at rest between patients and controls (1.1 ± 0.5 vs. 1.1 ± 0.3 ml/min/g, P = 0.85) whereas SSc patients showed statistically significantly lower MP during adenosine stress (3.1 ± 0.9 vs. 4.2 ± 1.3 ml/min/g, P = 0.008). Three out of the 19 SSc patients showed fibrosis in the right ventricle insertion points despite absence of PAH. None had signs of myocardial infarction. Conclusions: Patients with SSc have decreased MP during adenosine stress compared to healthy controls. Thus hypoperfusion at stress may be a sensitive marker of cardiac disease in SSc patients possibly signifying microvascular myocardial disease.
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| 10. |
- Hamberg, Viggo, et al.
(författare)
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Anti-Ro52 positivity is associated with progressive interstitial lung disease in systemic sclerosis-an exploratory study
- 2023
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Ingår i: Arthritis Research & Therapy. - : BioMed Central (BMC). - 1478-6362 .- 1478-6354. ; 25, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 11. |
- Hesselstrand, Roger, et al.
(författare)
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An open-label study to evaluate biomarkers and safety in systemic sclerosis patients treated with paquinimod
- 2021
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To evaluate the changes in disease-related biomarkers and safety of paquinimod, an oral immunomodulatory compound, in patients with systemic sclerosis (SSc). Methods: In this open-label, single-arm, multicenter study, SSc patients with a rapidly progressive disease received paquinimod for 8 weeks. Blood and skin biopsies were collected at baseline, during treatment, and at follow-up for the analyses of type I interferon (IFN) activity, chemokine (C-C motif) ligand 2 (CCL2), and the number of myofibroblasts. The safety of paquinimod was evaluated throughout the study. Results: Nine SSc patients were enrolled and completed the study treatment with paquinimod at 3 mg/day for 8 weeks. After the treatment, a reduction of type I IFN activity in the plasma from one patient with elevated baseline IFN activity was recorded. A trend towards reduced IFN activity in the skin after treatment was also observed in patients. The serum level of CCL2 was reduced in 7 of 9 patients after paquinimod treatment. There was a median reduction of 10% of the number of myofibroblasts in skin biopsies at week 8 compared to baseline. No change in modified Rodnan skin score and quality of life was detected in the study. Reported adverse events (AEs) were mild to moderate and expected with the most common being arthralgia (n = 3) and headache (n = 3), and C-reactive protein (CRP) increase. Conclusions: Analysis of biomarkers before and after treatment suggest reduced type I IFN activity and reduced number of myofibroblasts in lesional skin. Paquinimod was overall well tolerated with mild to moderate and expected AEs. Trial registration: ClinicalTrials.gov, NCT01487551. Registered on 7 September 2011.
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| 12. |
- Hjalmarsson, Clara, 1969, et al.
(författare)
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Early risk prediction in idiopathic versus connective tissue disease-associated pulmonary arterial hypertension : call for a refined assessment
- 2021
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Ingår i: ERJ Open Research. - : European Respiratory Society Publications. - 2312-0541. ; 7:3
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Tidskriftsartikel (refereegranskat)abstract
- Despite systematic screening and improved treatment strategies, the prognosis remains worse in patients with connective tissue disease-associated pulmonary arterial hypertension (CTD-PAH) compared to patients with idiopathic/hereditary pulmonary arterial hypertension (IPAH). We aimed to investigate differences in clinical characteristics, outcome and performance of the European Society of Cardiology (ESC)/ European Respiratory Society (ERS) risk stratification tool in these patient groups. This retrospective analysis included incident patients with CTD-PAH (n=197, of which 64 had interstitial lung disease, ILD) or IPAH (n=305) enrolled in the Swedish PAH Register (SPAHR) 2008-2019. Patients were classified as low, intermediate or high risk at baseline, according to the "SPAHR-equation". One-year survival, stratified by type of PAH, was investigated by Cox proportional regression. At baseline, CTD-PAH patients had lower diffusing capacity for carbon monoxide and lower haemoglobin but, at the same time, lower N-terminal prohormone-brain natriuretic peptide, longer 6 min walk distance, better haemodynamics and more often a low-risk profile. No difference in age, World Health Organisation functional class (WHO-FC) or renal function between groups was found. One-year survival rates were 75, 82 and 83% in patients with CTD-PAH with ILD, CTD-PAH without ILD and IPAH, respectively. The 1-year mortality rates for low-, intermediate- and high-risk groups in the whole cohort were 0, 18 and 34% (p<0.001), respectively. Corresponding percentages for CTD-PAH with ILD, CTD-PAH without ILD and IPAH patients were: 0, 26, 67% (p=0.008); 0, 19, 39% (p=0.004); and 0, 16, 29% (p=0.001), respectively. The ESC/ERS risk assessment tool accurately identified low-risk patients but underestimated the 1-year mortality rate of CTD-PAH and IPAH patients assessed as having intermediate risk at diagnosis.
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| 13. |
- Juhl, Pernille, et al.
(författare)
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Type III, IV, and VI Collagens Turnover in Systemic Sclerosis – a Longitudinal Study
- 2020
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Tissue turnover, especially in the skin, is altered in systemic sclerosis (SSc), leading to tissue accumulation. The objective was to examine type III, IV, and VI collagens turnovers in SSc and investigate longitudinal alterations in relation to modified Rodnan Skin Score (mRSS). We included patients fulfilling the 2013 ACR/EULAR criteria for SSc (limited cutaneous [lcSSc, n = 20], diffuse cutaneous SSc [dcSSc, n = 23]) and healthy controls (HC, n = 10). Biomarkers of type III, IV, and VI collagens formation (PRO-C3, PRO-C4, PRO-C6) and degradation (C3M, C4M, C6M) were measured in serum. The fibrotic index of the individual collagens (FICol) were calculated. The fibrotic index of type III and VI collagens (FICol3 and FICol6) were increased in dcSSc compared to lcSSc (FICol3: 1.4 vs. 0.8, P = 0.0001; FICol6: 1.2 vs. 0.9, P = 0.03). The fibrotic index of type IV collagen (FICol4) was not different between the groups but was 1.5 times higher than HC (HC: 6.9, lcSSc 10.4, dcSSc: 10.5). Both FICol3 and FICol6 correlated with mRSS with rho’s of 0.59 (P < 0.0001) and 0.35 (P = 0.04). Furthermore, FICol3 steadily decrease over the disease course. Examining collagen turnover and specific collagens could be beneficial in following patients’ skin fibrosis and possibly identifying progressors.
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| 14. |
- Sandqvist, Gunnel, et al.
(författare)
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The modified hand mobility in scleroderma test and skin involvement - A followup study
- 2016
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Ingår i: Journal of Rheumatology. - : The Journal of Rheumatology. - 0315-162X .- 1499-2752. ; 43:7, s. 1356-1362
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To study the change in the modified Hand Mobility in Scleroderma (mHAMIS) test from early to advanced stages of systemic sclerosis (SSc), and the relationship between mHAMIS and skin involvement during followup. Methods. This retrospective study includes 65 patients with baseline disease duration of . 3 years who were assessed with the mHAMIS test at baseline and at 1 or 2 predefined followup points (3.1.5 yrs and 5.1.9 yrs after disease onset). Studied measures were the modified Rodnan skin score (mRSS), mRSS of the hand, serum cartilage oligomeric matrix protein, and digital vascular lesions. Results. The mHAMIS and the mRSS hand changed synchronously during the first 5 years after disease onset (rs = 0.44, p = 0.001). In the group with high mHAMIS at baseline, both mHAMIS and mRSS hand improved significantly at the first followup (p <0.05), and the improvement sustained during the followup in the mRSS hand. Patients with antitopoisomerase I and anti-RNA polymerase III antibodies had significantly higher mHAMIS at baseline (p = 0.003) and at the second followup (p = 0.030) compared to patients with anticentromere antibodies. Patients with digital vascular lesions at baseline had significantly higher mHAMIS during the followup (p <0.05) compared to patients without. The mHAMIS improved significantly during the followup in patients with immunosuppressive treatment in early disease (p <0.05), but not in patients without this treatment. Conclusion. The mHAMIS reflects disease activity in fibrosis in early stages of SSc. In later stages it can be regarded as a measure of damage arising from fibrotic and vascular involvement, making it suitable as an endpoint in followup examinations.
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| 15. |
- Wildt, Marie, et al.
(författare)
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Treatment with mycophenolate mofetil is associated with improved nailfold vasculature in systemic sclerosis
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Ingår i: Rheumatology (Oxford, England). - 1462-0332.
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To investigate the evolution of nailfold capillary density in patients with systemic sclerosis (SSc) in relation to immunosupressive treatment and autoantibodies.METHODS: Prospective study cohort. Consecutive newly diagnosed SSc patients were included into this study who, in a retrospective review, had at least 2 nailfold capillary microscopy (NCM) measurements performed during the first 48 months of follow-up. Capillary density per 3 mm was measured with widefield NCM. Improvement of capillary density per finger and mean capillary density were analysed. Longitudinal measurements of mean capillary density were analysed by generalized estimating equation (GEE).RESULTS: Eighty patients (68 women, 12 men) met the inclusion criteria. The median follow-up time was 27 months. Twenty-eight patients had an improved capillary density in per finger analysis. Mycophenolate mofetil (MMF) was associated with less numbers of fingers that had worsened in capillary density. Anti-topoisomerase antibodies were associated with low mean capillary density. Anti-RNA polymerase III antibodies were associated with improvement and anti-centromere antibodies with worsening of capillary density in per finger analysis. MMF treatment was associated with less steep capillary density decline in a moderated GEE model including presence of anti-topoisomerase antibodies and the interaction of MMF with follow-up time.CONCLUSION: Nailfold capillary density improved over time in a substantial proportion of SSc patients. MMF treatment had a positive impact on the evolution of capillary density in these patients. SSc autoantibody phenotype may affect the capillary density development. The data support previous hypotheses that early immunosuppression may favourably affect vascular regeneration in SSc.
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| 16. |
- Wuttge, Dirk M., et al.
(författare)
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Circulating plasma microRNAs in systemic sclerosis-associated pulmonary arterial hypertension
- 2022
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Ingår i: Rheumatology (United Kingdom). - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:1, s. 309-318
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: SSc-associated pulmonary arterial hypertension (SSc-APAH) is a late but devastating complication of SSc. Early identification of SSc-APAH may improve survival. We examined the role of circulating miRNAs in SSc-APAH. Methods: Using quantitative RT-PCR the abundance of mature miRNAs in plasma was determined in 85 female patients with ACA-positive lcSSc. Twenty-two of the patients had SSc-APAH. Sixty-three SSc controls without PAH were matched for disease duration. Forty-six selected miRNA plasma levels were correlated with clinical data. Longitudinal samples were analysed from 14 SSc-APAH and 27 SSc patients. Results: The disease duration was 12 years for the SSc-APAH patients and 12.7 years for the SSc controls. Plasma expression levels of 11 miRNAs were lower in patients with SSc-APAH. Four miRNAs displayed higher plasma levels in SSc-APAH patients compared with SSc controls. There was significant difference between groups for miR-20a-5p and miR-203a-3p when correcting for multiple comparisons (P = 0.002 for both). Receiver operating characteristics curve showed AUC = 0.69-0.83 for miR-21-5p and miR-20a-5p or their combination. miR-20a-5p and miR-203a-3p correlated inversely with NT-pro-Brain Natriuretic Protein levels (r = -0.42 and -0.47). Mixed effect model analysis could not identify any miRNAs as predictor of PAH development. However, miR-20a-5p plasma levels were lower in the longitudinal samples of SSc-APAH patients than in the SSc controls. Conclusions: Our study links expression levels of the circulating plasma miRNAs, especially miR-20a-5p and miR-203a-3p, to the occurrence of SSc-APAH in female patients with ACA-positive lcSSc.
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| 17. |
- Wuttge, Dirk M., et al.
(författare)
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CXCL16/SR-PSOX is an interferon-gamma-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions
- 2004
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Ingår i: Arteriosclerosis, Thrombosis and Vascular Biology. - : American Heart Association. - 1079-5642 .- 1524-4636. ; 24:4, s. 750-755
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Atherosclerosis is an inflammatory disease. Several chemokines are important for monocyte/macrophage and T-cell recruitment to the lesion. CXCL16 is a recently discovered chemokine that is expressed in soluble and transmembrane forms, ligates CXCR6 chemokine receptor, and guides migration of activated Th1 and Tc1 cells. It is identical to scavenger receptor SR-PSOX, which mediates uptake of oxidized low-density lipoprotein. We investigated whether CXCL16 expression is controlled by interferon-gamma (IFN-gamma)-cytokine abundant in atherosclerotic lesions. METHODS AND RESULTS: CXCL16 and CXCR6 expression was identified by polymerase chain reaction and histochemistry in atherosclerotic lesions from humans and apolipoprotein-E-deficient mice. In vitro IFN-gamma induced CXCL16 in human monocytic THP-1 cells and primary human monocytes, which led to increased uptake of oxidized low-density lipoprotein in THP-1 cells, which could be blocked by peptide antibodies against CXCL16. In vivo IFN-gamma induced CXCL16 expression in murine atherosclerotic lesions. CONCLUSIONS: We demonstrate a novel role of IFN-gamma in foam cell formation through upregulation of CXCL16/SR-PSOX. CXCR6 expression in the plaque confirms the presence of cells able to respond to CXCL16. Therefore, this chemokine/scavenger receptor could serve as a molecular link between lipid metabolism and immune activity in the atherosclerotic lesion.
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| 18. |
- Wuttge, Dirk M., et al.
(författare)
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Induction of CD36 by all-trans retionic acid : retinoic acid receptor signaling in the pathogenesis of atherosclerosis
- 2001
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Ingår i: The FASEB Journal. - : Wiley. - 0892-6638 .- 1530-6860. ; 15:7, s. 1221-3
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Tidskriftsartikel (refereegranskat)abstract
- Scavenger receptors mediating the uptake of oxidized low-density lipoproteins (oxLDL) by macrophages play a crucial role in foam cell formation during atherosclerosis. One member of this receptor family, the thrombospondin receptor CD36, has recently been shown to mediate a major part of the oxLDL-induced aggravation of atherosclerotic lesions. Here, we show that the expression of CD36 protein and mRNA in human monocytic THP-1 cells is increased by alltrans retinoic acid (atRA), a derivative of the essential Vitamin A, which leads to increased uptake of oxLDL. CD3106, a specific antagonist at the retinoic acid receptor (RAR), inhibited the atRA-induced CD36 expression, whereas the RAR-specific agonist CD367 induced CD36 to the same degree as atRA. This indicates an RAR-mediated CD36 induction. AtRA and oxLDL had synergistic effects in up-regulating CD36 when in both THP-1 cells and primary monocytes. Applying a sensitive RAR-GAL-4 reporter assay, we could demonstrate RAR ligands in human atherosclerotic lesions. In addition, immunohistochemistry showed RAR- which indicates that atRA may contribute to foam cell formation and the progress of atherosclerosis.
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| 19. |
- Wuttge, Dirk M., et al.
(författare)
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Validation of the Swedish version of PROMIS-29v2 and FACIT-Dyspnea Index in patients with systemic sclerosis
- 2023
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Ingår i: Disability and Rehabilitation. - : Informa UK Limited. - 0963-8288 .- 1464-5165. ; 45:15, s. 2517-2525
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To evaluate the reliability, internal consistency, and construct validity of the Swedish versions of PROMIS-29 and Functional Assessment of Chronic Illness Therapy-Dyspnea (FACIT-Dyspnea) instruments in patients with systemic sclerosis (SSc). Methods In a cross-sectional study, consecutive SSc patients completed a paper-based survey. Internal consistency was assessed using Cronbach's alpha. Test-retest reliability was tested employing weighted Kappa (K-w) and intra-class correlation coefficient (ICC). Construct validity was evaluated by hypotheses testing using RAND-36, MRC Dyspnea score, Scleroderma Health Assessment Questionnaire (SHAQ) and clinical measurements. Results Forty-nine patients (86% female; 73% limited cutaneous SSc) completed the survey. The mean disease duration was 11 years and mean SHAQ was 0.5. Internal consistency and test-retest reliability were good with the exception of PROMIS-29 anxiety. PROMIS-29, FACIT-Dyspnea, and Functional limitation showed strong correlations to corresponding RAND-36 domains (|r(s)|=0.67 to -0.85). Relevant PROMIS-29 domains, FACIT-Dyspnea and Functional limitation correlated strongly to SHAQ and VAS overall disease severity (|r(s)|=0.60 to -0.75). Ceiling effects (>15%) were found in six PROMIS-29 domains and in both FACIT-Dyspnea and Functional limitations. Four (4/5) hypotheses were confirmed. Conclusions PROMIS-29 and FACIT-Dyspnea meet the requirements for reliability and have adequate construct validity in Swedish patients with SSc.
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