| 1. |
- Westergren-Thorsson, Gunilla, et al.
(author)
-
Increased deposition of glycosaminoglycans and altered structure of heparan sulfate in idiopathic pulmonary fibrosis
- 2017
-
In: International Journal of Biochemistry & Cell Biology. - : Elsevier BV. - 1357-2725 .- 1878-5875. ; 83, s. 27-38
-
Journal article (peer-reviewed)abstract
- Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant deposition of extracellular matrix (ECM) constituents, including glycosaminoglycans (GAGs), that may play a role in remodelling processes by influencing critical mediators such as growth factors. We hypothesize that GAGs may be altered in IPF and that this contribute to create a pro-fibrotic environment. The aim of this study was therefore to examine the fine structure of heparan sulfate (HS), chondroitin/dermatan sulfate (CS/DS) and hyaluronan (HA) in lung samples from IPF patients and from control subjects. GAGs in lung samples from severe IPF patients and donor lungs were analyzed with HPLC. HS was assessed by immunohistochemistry and collagen was quantified as hydroxyproline content. The total amount of HS, CS/DS and HA was increased in IPF lungs but there was no significant difference in the total collagen content. We found a relative increase in total sulfation of HS due to increment of 2-O, 6-O and N-sulfation and a higher proportion of sulfation in CS/DS. Highly sulfated HS was located in the border zone between denser areas and more normal looking alveolar parenchyma in basement membranes of blood vessels and airways, that were immuno-positive for perlecan, as well as on the cell surface of spindle-shaped cells in the alveolar interstitium. These findings show for the first time that both the amount and structure of glycosaminoglycans are altered in IPF. These changes may contribute to the tissue remodelling in IPF by altering growth factor retention and activity, creating a pro-fibrotic ECM landscape. (C) 2016 The Authors. Published by Elsevier Ltd.
|
|
| 2. |
- Dinsdale, Graham, et al.
(author)
-
Intra-and inter-observer reliability of nailfold videocapillaroscopy - A possible outcome measure for systemic sclerosis-related microangiopathy
- 2017
-
In: Microvascular Research. - : Elsevier BV. - 1095-9319 .- 0026-2862. ; 112, s. 1-6
-
Journal article (peer-reviewed)abstract
- OBJECTIVES: Our aim was to assess the reliability of nailfold capillary assessment in terms of image evaluability, image severity grade ('normal', 'early', 'active', 'late'), capillary density, capillary (apex) width, and presence of giant capillaries, and also to gain further insight into differences in these parameters between patients with systemic sclerosis (SSc), patients with primary Raynaud's phenomenon (PRP) and healthy control subjects.METHODS: Videocapillaroscopy images (magnification 300×) were acquired from all 10 digits from 173 participants: 101 patients with SSc, 22 with PRP and 50 healthy controls. Ten capillaroscopy experts from 7 European centres evaluated the images. Custom image mark-up software allowed extraction of the following outcome measures: overall grade ('normal', 'early', 'active', 'late', 'non-specific', or 'ungradeable'), capillary density (vessels/mm), mean vessel apical width, and presence of giant capillaries.RESULTS: Observers analysed a median of 129 images each. Evaluability (i.e. the availability of measures) varied across outcome measures (e.g. 73.0% for density and 46.2% for overall grade in patients with SSc). Intra-observer reliability for evaluability was consistently higher than inter- (e.g. for density, intra-class correlation coefficient [ICC] was 0.71 within and 0.14 between observers). Conditional on evaluability, both intra- and inter-observer reliability were high for grade (ICC 0.93 and 0.78 respectively), density (0.91 and 0.64) and width (0.91 and 0.85).CONCLUSIONS: Evaluability is one of the major challenges in assessing nailfold capillaries. However, when images are evaluable, the high intra- and inter-reliabilities suggest that overall image grade, capillary density and apex width have potential as outcome measures in longitudinal studies.
|
|
| 3. |
- Dinsdale, Graham, et al.
(author)
-
Nailfold capillaroscopy-how many fingers should be examined to detect abnormality?
- 2019
-
In: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 58:2, s. 284-288
-
Journal article (peer-reviewed)abstract
- Objectives: Nailfold capillaroscopy is being increasingly used by rheumatologists in the diagnosis of SSc. However, assessment of all nailfolds can be time-consuming in a busy outpatient clinic. Our aim was to answer the question as to how many (and which) fingers a clinician should routinely assess to capture accurately the true state. Methods: A total of 2994 assessments (by an international panel of expert observers) of 1600 images from 173 participants (101 with SSc, 22 with primary RP and 50 healthy controls) were included in this analysis. Seven single-finger or finger combinations (derived from the middle and ring fingers) were then tested for sensitivity for the presence of two markers of capillary abnormality [presence of giant capillaries and an SSc grade (early, active or late)] compared with assessment of all eight fingers. Results: For the eight-finger gold standard, sensitivity against the diagnostic criteria was 74.6% (53.0% for the presence of giants alone and 73.1% for image grade alone). Examining only one finger gave low sensitivity (ranging from right middle 31.7% to left ring 46.6%). Examining both ring fingers gave a sensitivity of 59.8%, whereas examining the four-finger combination of both ring and both middle fingers gave a sensitivity of 66.7%. Conclusion: During routine capillaroscopic examination, ideally all eight nailbeds (excluding thumbs) should be examined, otherwise some abnormalities will be missed. Examining only four fingers reduces capillaroscopy sensitivity.
|
|
| 4. |
- Dinsdale, Graham, et al.
(author)
-
Quantitative outcome measures for systemic sclerosis-related Microangiopathy – Reliability of image acquisition in Nailfold Capillaroscopy
- 2017
-
In: Microvascular Research. - : Elsevier BV. - 0026-2862. ; 113, s. 56-59
-
Journal article (peer-reviewed)abstract
- Background Nailfold capillaroscopic parameters hold increasing promise as outcome measures for clinical trials in systemic sclerosis (SSc). Their inclusion as outcomes would often naturally require capillaroscopy images to be captured at several time points during any one study. Our objective was to assess repeatability of image acquisition (which has been little studied), as well as of measurement. Method 41 patients (26 with SSc, 15 with primary Raynaud's phenomenon) and 10 healthy controls returned for repeat high-magnification (300 ×) videocapillaroscopy mosaic imaging of 10 digits one week after initial imaging (as part of a larger study of reliability). Images were assessed in a random order by an expert blinded observer and 4 outcome measures extracted: (1) overall image grade and then (where possible) distal vessel locations were marked, allowing (2) vessel density (across the whole nailfold) to be calculated (3) apex width measurement and (4) giant vessel count. Intra-rater, intra-visit and intra-rater inter-visit (baseline vs. 1 week) reliability were examined in 475 and 392 images respectively. A linear, mixed-effects model was used to estimate variance components, from which intra-class correlation coefficients (ICCs) were determined. Results Intra-visit and inter-visit reliability estimates (ICCs) were (respectively): overall image grade, 0.97 and 0.90; vessel density, 0.92 and 0.65; mean vessel width, 0.91 and 0.79; presence of giant capillary, 0.68 and 0.56. These estimates were conditional on each parameter being measurable. Conclusion Within-operator image analysis and acquisition are reproducible. Quantitative nailfold capillaroscopy, at least with a single observer, provides reliable outcome measures for clinical studies including randomised controlled trials.
|
|
| 5. |
|
|
| 6. |
- Hallgren, Oskar, et al.
(author)
-
Splicosomal and serine and arginine-rich splicing factors as targets for TGF-β
- 2012
-
In: Fibrogenesis & tissue repair. - : Springer Science and Business Media LLC. - 1755-1536. ; 5:1, s. 6-6
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Transforming growth factor-β1 (TGF-β1) is a potent regulator of cell growth and differentiation. TGF-β1 has been shown to be a key player in tissue remodeling processes in a number of disease states by inducing expression of extracellular matrix proteins. In this study a quantitative proteomic analysis was undertaken to investigate if TGF-β1 contributes to tissue remodeling by mediating mRNA splicing and production of alternative isoforms of proteins.METHODOLOGY/PRINCIPAL FINDINGS: The expression of proteins involved in mRNA splicing from TGF-β1-stimulated lung fibroblasts was compared to non-stimulated cells by employing isotope coded affinity tag (ICATTM) reagent labeling and tandem mass spectrometry. A total of 1733 proteins were identified and quantified with a relative standard deviation of 11% +/- 8 from enriched nuclear fractions. Seventy-six of these proteins were associated with mRNA splicing, including 22 proteins involved in splice site selection. In addition, TGF-β1 was observed to alter the relative expression of splicing proteins that may be important for alternative splicing of fibronectin. Specifically, TGF-β1 significantly induced expression of SRp20, and reduced the expression of SRp30C, which has been suggested to be a prerequisite for generation of alternatively spliced fibronectin. The induction of SRp20 was further confirmed by western blot and immunofluorescence.CONCLUSIONS: The results show that TGF-β1 induces the expression of proteins involved in mRNA splicing and RNA processing in human lung fibroblasts. This may have an impact on the production of alternative isoforms of matrix proteins and can therefore be an important factor in tissue remodeling and disease progression.
|
|
| 7. |
- Hamberg, Viggo, et al.
(author)
-
Anti-Ro52 positivity is associated with progressive interstitial lung disease in systemic sclerosis-an exploratory study
- 2023
-
In: Arthritis Research & Therapy. - : BioMed Central (BMC). - 1478-6362 .- 1478-6354. ; 25, s. 1-13
-
Journal article (peer-reviewed)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.
|
|
| 8. |
- Hesselstrand, Roger, et al.
(author)
-
Biomarkers from bronchoalveolar lavage fluid in systemic sclerosis patients with interstitial lung disease relate to severity of lung fibrosis.
- 2013
-
In: Respiratory Medicine. - : Elsevier BV. - 1532-3064 .- 0954-6111. ; 107:7, s. 1079-1086
-
Journal article (peer-reviewed)abstract
- OBJECTIVES: Decision on treatment of systemic sclerosis (SSc) related interstitial lung disease (ILD) largely relies on the findings on high resolution computed tomography (HRCT) and there is a need for improvement in assessment of the fibrotic activity. The objectives of this study were to study biomarkers in bronchoalveolar lavage fluid (BALF) from SSc patients with ILD and to relate the findings to the severity and activity of lung fibrosis. METHODS: Fifteen patients with early SSc and 12 healthy controls were subjected to BAL. Cell counts and analyses of CXCL5, CXCL8 and S100A8/A9 were performed in BALF and serum. COMP and KL-6 were measured in serum. HRCT of lungs was quantified for ground glass opacities (GGO), reticulation and traction bronchiectases. RESULTS: BALF concentrations of CXCL8 (p < 0.001), CXCL5 (p = 0.002) and S100A8/A9 (p = 0.016) were higher in patients than controls. Serum KL-6 (p < 0.001) was increased in SSc patients and correlated with BALF concentration of eosinophils (rS = 0.57, p = 0.027). Patients with more widespread GGO on HRCT were characterised in BALF by a higher eosinophil count (p = 0.002) and in serum by higher KL-6 (p = 0.008). Patients with more fibrosis were characterised in BALF by higher eosinophil count (p = 0.014), higher CXCL8 (p = 0.005) and S100A8A/A9 (p = 0.014) concentration and in serum by a higher serum COMP (p = 0.023). CONCLUSIONS: In SSc related ILD, biomarkers from BALF and serum correlate to findings on HRCT suggesting usefulness as markers of presence and extent of lung fibrosis.
|
|
| 9. |
- Hesselstrand, Roger, et al.
(author)
-
High frequency ultrasound of skin involvement in systemic sclerosis - a follow-up study.
- 2015
-
In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 17:1
-
Journal article (peer-reviewed)abstract
- High-frequency ultrasound offers a potential for objective and quantitative assessment of skin thickness and skin echogenicity in systemic sclerosis (SSc). Few studies have however assessed the longitudinal changes of skin involvement using ultrasound. The aim of the study was to investigate changes in skin thickness in early SSc using high frequency ultrasound during one year of follow-up in comparison to other measurements of skin fibrosis.
|
|
| 10. |
- Hesselstrand, Roger, et al.
(author)
-
High-frequency ultrasound of skin involvement in systemic sclerosis reflects oedema, extension and severity in early disease.
- 2008
-
In: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 47:1, s. 84-87
-
Journal article (peer-reviewed)abstract
- OBJECTIVE: The aim was to compare skin assessment by palpation and by high-frequency ultrasound in patients with SSc with disease duration <2 yrs. METHODS: Skin thickness and skin echogenicity were measured by 20 MHz ultrasound at five different anatomical sites in 106 individuals within 2 yrs from the first non-Raynaud's symptom and compared with the modified Rodnan skin score (mRss). RESULTS: The patients with short disease duration were characterized by high skin thickness and low skin echogenicity, which correlated inversely, reflecting oedema. Patients with diffuse skin involvement displayed higher skin thickness and lower skin echogenicity than did patients with limited skin involvement. The ultrasound measurements correlated to the local mRss from the corresponding anatomical region and also to the total mRss. However, there was a considerable overlap in both skin thickness and skin echogenicity between different local mRss at all five anatomical sites. Skin involvement of the chest could be detected earlier by ultrasound than by palpation. CONCLUSION: In SSc patients with short disease duration, high-frequency ultrasound can identify the oedematous phase that may precede palpable skin involvement and may thus be useful to identify patients with diffuse skin involvement very early in the disease process. Ultrasound measurements also reflect the severity of the overall skin involvement.
|
|
| 11. |
- Hesselstrand, Roger, et al.
(author)
-
Survival in patients with pulmonary arterial hypertension associated with systemic sclerosis from a Swedish single centre: prognosis still poor and prediction difficult
- 2011
-
In: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 40:2, s. 127-132
-
Journal article (peer-reviewed)abstract
- Objectives: To describe the survival rate in a cohort of systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) and to evaluate possible predictors for SSc-PAH in a cohort of SSc patients. Methods: Thirty patients with SSc-PAH and 150 SSc patients without PAH were included. Survival and survival on therapy were calculated. Clinical features at baseline were correlated to the risk for development of PAH during follow-up. Results: The 1-, 2-, 3-, and 4-year survival rates were 86, 59, 39, and 22%, respectively, from diagnosis of PAH. The hazard ratio for total mortality in the SSc-PAH group was 3.2 [95% confidence interval (CI) 1.8-5.7] compared to SSc without PAH (p < 0.001). Risk factors at baseline for the development of PAH were: limited skin involvement, low diffusing capacity of the lung for carbon monoxide (DLCO), high N-terminal pro-brain natriuretic peptide (NTProBNP), increased estimated systolic pulmonary arterial pressure (ESPAP), and the presence of teleangiectases. Severe peripheral vascular disease requiring iloprost treatment during follow-up was associated with an eightfold increased risk of PAH. Conclusion: Despite modern treatment and yearly screening by echocardiography, the survival in SSc-PAH is still low in our cohort. The identified risk factors should be assessed to select patients eligible for right heart catheterization (RHC) to make an earlier diagnosis.
|
|
| 12. |
- Hesselstrand, Roger, et al.
(author)
-
The association between changes in skin echogenicity and the fibroblast production of biglycan and versican in systemic sclerosis
- 2002
-
In: Clinical and Experimental Rheumatology. - 1593-098X. ; 20:3, s. 301-308
-
Journal article (peer-reviewed)abstract
- Objective To investigate a possible association between the longitudinal changes in skin involvement and the fibroblast production of proteoglycans in vitro, among patients with early and untreated systemic sclerosis (SSc). Methods In 11 patients, 6 with diffuse cutaneous systemic sclerosis (dSSc) and 5 with limited cutaneous systemic sclerosis (lSSc), and in 6 controls skin thickness and skin echogenicity, of the forearm was measured by high frequency (20 MHz) ultrasound, A skin biopsy was taken from the area of the ultrasound measurements, and from cultivated fibroblasts the production of the proteoglycans versican, perlecan, biglycan and decorin were measured. To investigate longitudinal changes in skin involvement, the ultrasound examination was repeated after 1-3 years. Results Compared to controls, SSc Patients had increased skin thickness at the first evaluation. Patients with dSSc had lower skin echogenicity than both patients with ISSc and the controls. Patients with greater changes in skin thickness and skin echogenicity produced more versican, whereas the production of biglycan and decorin was higher only, in patients with greater changes in skin echogenicity. There was a negative correlation between fibroblast production of biglycan and disease duration. Conclusion High fibroblast synthesis of the proteoglycans versican and biglycan is associated with changes in skin echogenicity and may predict more progressive skin sclerosis in SSc.
|
|
| 13. |
- Hofstee, Herman M A, et al.
(author)
-
A multicentre study on the reliability of qualitative and quantitative nail-fold videocapillaroscopy assessment.
- 2012
-
In: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 51:4, s. 749-755
-
Journal article (peer-reviewed)abstract
- Objective. To investigate the inter- and intra-observer reliability of both qualitative and quantitative parameters used in the assessment of nail-fold capillaroscopy images.Methods. Fifty mosaic nail-fold images of healthy controls (n = 10), patients with primary RP (n = 10) and SSc (n = 30) were assessed in random order by two blinded observers on two occasions at centres in Sweden, UK and The Netherlands. Each image was therefore scored by six observers twice.Results. Inter- and intra-observer reliability of quantitative parameters showed substantial to almost perfect agreement [inter- and intra-observer weighted κ's for the number of widened capillaries was 0.75 and 0.87 and giant capillaries was 0.84 and 0.92, intra-class correlation coefficients (ICCs) for capillary density was 0.87 and 0.92 and total loop width was 0.94 and 0.98, respectively]. Qualitative parameters including architecture, avascularity, haemorrhage, crossed, ramified and bushy capillaries showed moderate to substantial inter-observer reproducibility (weighted κ ranging from 0.47 to 0.73), and substantial intra-observer repeatability (weighted κ ranging from 0.71 to 0.80), whereas the scoring of tortuous and bizarre capillaries showed poor inter-observer and substantial intra-observer agreement (inter-observer weighted κ's was 0.39 and 0.21 and intra-observer weighted κ's was 0.68 and 0.76, respectively).Conclusion. All quantitative and certain qualitative parameters are highly reliable in terms of inter- and intra-observer agreement. A combination of parameters with the highest reliability should be incorporated into future capillaroscopic scoring systems in studies of prediction and monitoring of SSc spectrum disorders.
|
|
| 14. |
|
|
| 15. |
- Kadefors, Måns, et al.
(author)
-
Dipeptidyl peptidase 4 expression is not associated with an activated fibroblast phenotype in idiopathic pulmonary fibrosis
- 2022
-
In: Frontiers in Pharmacology. - : Frontiers Media SA. - 1663-9812. ; 13, s. 1-12
-
Journal article (peer-reviewed)abstract
- Dipeptidyl peptidase 4 (DPP4) has been proposed as a marker for activated fibroblasts in fibrotic disease. We aimed to investigate whether a profibrotic DPP4 phenotype is present in lung tissue from patients with idiopathic pulmonary fibrosis (IPF). The presence of DPP4 + fibroblasts in normal and IPF lung tissue was investigated using flow cytometry and immunohistology. In addition, the involvement of DPP4 in fibroblast activation was examined in vitro, using CRISPR/Cas9 mediated genetic inactivation to generate primary DPP4 knockout lung fibroblasts. We observed a reduced frequency of primary DPP4 + fibroblasts in IPF tissue using flow cytometry, and an absence of DPP4 + fibroblasts in pathohistological features of IPF. The in vivo observations were supported by results in vitro showing a decreased expression of DPP4 on normal and IPF fibroblasts after profibrotic stimuli (transforming growth factor β) and no effect on the expression of activation markers (α-smooth muscle actin, collagen I and connective tissue growth factor) upon knockout of DPP4 in lung fibroblasts with or without activation with profibrotic stimuli.
|
|
| 16. |
- Larsen, Kristoffer, et al.
(author)
-
Functional and phenotypical comparison of myofibroblasts derived from biopsies and bronchoalveolar lavage in mild asthma and scleroderma
- 2006
-
In: Respiratory Research. - : Springer Science and Business Media LLC. - 1465-9921 .- 1465-993X. ; 7
-
Journal article (peer-reviewed)abstract
- Background: Activated fibroblasts, which have previously been obtained from bronchoalveolar lavage fluid (BALF), are proposed to be important cells in the fibrotic processes of asthma and scleroderma (SSc). We have studied the motility for BALF derived fibroblasts in patients with SSc that may explain the presence of these cells in the airway lumen. Furthermore, we have compared phenotypic alterations in activated fibroblasts from BALF and bronchial biopsies from patients with mild asthma and SSc that may account for the distinct fibrotic responses. Methods: Fibroblasts were cultured from BALF and bronchial biopsies from patients with mild asthma and SSc. The motility was studied using a cell migration assay. Western Blotting was used to study the expression of alpha-smooth muscle actin (alpha-SMA), ED-A fibronectin, and serine arginine splicing factor 20 (SRp20). The protein expression pattern was analyzed to reveal potential biomarkers using two-dimensional electrophoresis (2-DE) and sequencing dual matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-TOF). The Mann-Whitney method was used to calculate statistical significance. Results: Increased migration and levels of ED-A fibronectin were observed in BALF fibroblasts from both groups of patients, supported by increased expression of RhoA, Rac1, and the splicing factor SRp20. However, these observations were exclusively accompanied by increased expression of alpha-SMA in patients with mild asthma. Compared to BALF fibroblasts in mild asthma, fibroblasts in SSc displayed a differential protein expression pattern of cytoskeletal- and scavenger proteins. These identified proteins facilitate cell migration, oxidative stress, and the excessive deposition of extracellular matrix observed in patients with SSc. Conclusion: This study demonstrates a possible origin for fibroblasts in the airway lumen in patients with SSc and important differences between fibroblast phenotypes in mild asthma and SSc. The findings may explain the distinct fibrotic processes and highlight the motile BALF fibroblast as a potential target cell in these disorders.
|
|
| 17. |
- Larsen, Kristoffer, et al.
(author)
-
Presence of activated mobile fibroblasts in bronchoalveolar lavage from patients with mild asthma
- 2004
-
In: American Journal of Respiratory and Critical Care Medicine. - 1535-4970. ; 170:10, s. 1049-1056
-
Journal article (peer-reviewed)abstract
- Activated fibroblasts are suggested to be involved in the deposition of extracellular matrix in the formation of peribronchial fibrosis in asthma. We report the novel finding of activated elongated fibroblasts accompanied by elevated numbers of eosinophils in bronchoalveolar lavage fluid from 5 out of 12 patients with mild asthma (= 42%), whereas no fibroblasts were observed in the control subjects without asthma (n = 17). The elongated fibroblasts migrated twice as far when compared with fibroblasts from corresponding bronchial biopsies from the same patients, accompanied by an induced expression of RhoA and Rac1, indicating that the increased expression of these proteins are linked to increased migratory capabilities. Moreover, the elongated fibroblasts had an elevated production of the proteoglycans biglycan, versican, perlecan, and decorin, which correlated to an active cytoplasm in these cells. Differential expression patterns between the two fibroblast groups in motility-regulating proteins, such as cofilin, nuclear chloride ion channel protein, and heat-shock protein 20, were identified by two-dimensional electrophoresis and mass spectrometry. These findings indicate the presence of activated and mobile fibroblasts accompanied by an induced inflammatory response outside the airway epithelium in patients with mild asthma, results that may play a role in formation of airway fibrosis.
|
|
| 18. |
- Miehlke, Stephan, et al.
(author)
-
European guidelines on microscopic colitis : United European Gastroenterology (UEG) and European Microscopic Colitis Group (EMCG) statements and recommendations
- 2021
-
In: United European Gastroenterology journal. - : Sage Publications. - 2050-6406 .- 2050-6414. ; 9:1, s. 13-37
-
Research review (peer-reviewed)abstract
- Introduction: Microscopic colitis is a chronic inflammatory bowel disease characterised by normal or almost normal endoscopic appearance of the colon, chronic watery, non-bloody diarrhoea and distinct histological abnormalities, which identify three histological subtypes, the collagenous colitis, the lymphocytic colitis and the incomplete microscopic colitis. With ongoing uncertainties and new developments in the clinical management of microscopic colitis, there is a need for evidence-based guidelines to improve the medical care of patients suffering from this disorder.Methods: Guidelines were developed by members from the European Microscopic Colitis Group and United European Gastroenterology in accordance with the Appraisal of Guidelines for Research and Evaluation II instrument. Following a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the certainty of the evidence. Statements and recommendations were developed by working groups consisting of gastroenterologists, pathologists and basic scientists, and voted upon using the Delphi method.Results: These guidelines provide information on epidemiology and risk factors of microscopic colitis, as well as evidence-based statements and recommendations on diagnostic criteria and treatment options, including oral budesonide, bile acid binders, immunomodulators and biologics. Recommendations on the clinical management of microscopic colitis are provided based on evidence, expert opinion and best clinical practice.Conclusion: These guidelines may support clinicians worldwide to improve the clinical management of patients with microscopic colitis.
|
|
| 19. |
- Santiago, Tânia, et al.
(author)
-
Recommendations for the execution and reporting of skin ultrasound in systemic sclerosis : an international collaboration under the WSF skin ultrasound group
- 2022
-
In: RMD Open. - : BMJ. - 2056-5933. ; 8:2
-
Research review (peer-reviewed)abstract
- Objective Ultrasound is a promising tool to foster much-needed improvement of skin assessment in systemic sclerosis (SSc). Our aim was to develop evidence and expert opinion-based recommendations to promote the standardisation and harmonisation of technical execution and reporting of skin ultrasound studies in SSc. Methods A multidisciplinary task force of 16 members from five European countries and Japan was convened under the auspices of World Scleroderma Foundation. First, a systematic literature review (SLR) was performed. Then, each member proposed and formulated items to the overarching principles, recommendations and research agenda. Two rounds of mails exchange for consensus as well as an on-line meeting were performed to debate and refine the proposals. Two Delphi rounds of voting resulted in the final recommendations. Levels of evidence and strengths of recommendations were assigned, and task force members voted anonymously on the level of agreement with each of the items. Results Five overarching principles and seven recommendations were developed, based on an SLR and expert opinion, through consensus procedures. The overarching principles highlight the promising role of skin ultrasound in SSc assessment, the need for standardisation of technical aspects, sufficient training and adequate equipment. The recommendations provide standards for the execution and reporting of skin ultrasound in SSc. The research agenda includes the need for more research into unmet needs according to Outcome Measures in Rheumatology Algorithm requirements. Conclusion These are the first recommendations providing guidance on the execution and reporting of skin ultrasound in SSc patients, aiming at improving the interpretability, reliability and generalisability of skin ultrasound, thus consolidating its role in research and practice.
|
|
| 20. |
- Santiago, Tânia, et al.
(author)
-
Ultrasound and elastography in the assessment of skin involvement in systemic sclerosis : A systematic literature review focusing on validation and standardization – WSF Skin Ultrasound Group
- 2022
-
In: Seminars in Arthritis and Rheumatism. - : Elsevier BV. - 0049-0172. ; 52
-
Research review (peer-reviewed)abstract
- Objective: To summarize the published evidence in the literature on the role of ultrasound and elastography to assess skin involvement in systemic sclerosis (SSc). Methods: A systematic literature review (SLR) was performed within the “Skin Ultrasound Working Group” of the World Scleroderma Foundation, according to the Cochrane Handbook. A search was conducted in Pubmed, Cochrane Library and Embase databases from 1/1/1979 to 31/5/2021, using the participants, intervention, comparator and outcomes (PICO) framework. Only full-text articles involving adults, reported in any language, assessing ultrasound to quantify skin pathology in SSc patients. Two reviewers performed the assessment of risk of bias, data extraction and synthesis, independently. Results: Forty-six studies out of 3248 references evaluating skin ultrasound and elastography domains were included. B-mode ultrasound was used in 30 studies (65.2%), elastography in nine (19.6%), and both methods in seven (15.2%). The ultrasound outcome measure domains reported were thickness (57.8%) and echogenicity (17.2%); the elastography domain was stiffness (25%). Methods used for image acquisition and analysis were remarkably heterogeneous and frequently under-reported, precluding data synthesis across studies. The same applies to contextual factors and feasibility. Our data syntheses indicated evidence of good reliability and convergent validity for ultrasound thickness evaluation against mRSS and skin histological findings. Stiffness and echogenicity have limited evidence for validity against histological findings. Evidence for sensitivity to change, test-retest reliability, clinical trial discrimination or thresholds of meaning is limited or absent for reported ultrasound domains. Conclusion: Ultrasound is a valid and reliable tool for skin thickness measurement in SSc but there are significant knowledge gaps regarding skin echogenicity assessment by ultrasound and skin stiffness evaluation by elastography in terms of feasibility, validity and discrimination. Standardization of image acquisition and analysis is needed to foster progress.
|
|
| 21. |
- Scheja, Agneta, et al.
(author)
-
BAL fluid derived fibroblasts differ from biopsy derived fibroblasts in systemic sclerosis.
- 2007
-
In: European Respiratory Journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 29:3, s. 446-452
-
Journal article (peer-reviewed)abstract
- Growth of fibroblasts from bronchoalveolar lavage fluid (BALF) in patients with systemic sclerosis (SSc) has previously been described. The purpose of the present study was to characterise fibroblasts from BALF and bronchial biopsies from SSc patients with alveolitis and from controls, to analyse fibroblast proliferation, migration, stress fibres and proteoglycan production. BALF and bronchial biopsies were collected from 10 patients with SSc and alveolitis and from 15 controls. Outgrowth of fibroblasts was observed from the BALF of four patients, particularly in those with a markedly increased percentage of eosinophils in BALF, but not in any member of the control group. Increased levels of granulocyte-macrophage colony-stimulating factor, correlating with the percentage of eosinophils in BALF, were found in patients when compared with controls. Fibroblasts from BALF showed an elongated, mobile phenotype and increased proteoglycan production compared to the corresponding biopsy fibroblasts. In conclusion, outgrowth of fibroblasts with an altered phenotype is reported from bronchoalveolar lavage fluid in systemic sclerosis patients with alveolitis and an increased percentage of eosinophils in the bronchoalveolar lavage fluid. These findings indicate a possible role for eosinophil-fibroblast interaction in pulmonary fibrosis in systemic sclerosis.
|
|
| 22. |
|
|
| 23. |
- Scheja, Agneta, et al.
(author)
-
Progressive capillary loss over a decade in patients with systemic sclerosis, in particular in patients with early digital ischaemic manifestations.
- 2011
-
In: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 40, s. 457-461
-
Journal article (peer-reviewed)abstract
- Objective: Characteristic capillary abnormalities occur early in systemic sclerosis (SSc). Our aim was to study the longitudinal development of capillary density in SSc patients. Methods: Forty-eight consecutive patients with SSc fulfilling a follow-up of at least 8 years were retrospectively analysed for capillary loss over the observation period. Eleven had diffuse cutaneous SSc (dcSSc) and 37 limited cutaneous SSc (lcSSc). The median disease duration at first assessment was 2.5 years. Capillary density was determined by direct counting of capillaries in the distal row on eight fingers in a stereo-zoom microscope at 20× magnification. Results: Capillary density decreased over the observation period in dcSSc (from median 5.1 to 4.4 loops/mm, p < 0.05) and in lcSSc (from 5.1 to 4.2 loops/mm, p < 0.001). No significant difference was found between the two forms at start or at follow-up. Digital ischaemic manifestations had already been found at the first assessment in 19 patients. They did not differ in capillary density from those without ischaemic manifestations at the first assessment (5.0 and 5.3 loops/mm), but did differ at follow-up (3.6 and 4.7 loops/mm, p < 0.001). Capillary loss was more pronounced in patients who already had digital ischaemic manifestations at the first assessment compared to those without (p < 0.02). Conclusion: In SSc, early digital ischaemic manifestations may precede a subsequent progressive capillary loss. The association between capillary loss and serious internal vascular complications remains to be studied.
|
|
| 24. |
|
|
| 25. |
- Scheja, Agneta, et al.
(author)
-
Von Willebrand factor propeptide as a marker of disease activity in systemic sclerosis (scleroderma)
- 2001
-
In: Arthritis Research & Therapy. - : Springer Science and Business Media LLC. - 1465-9913 .- 1465-9905. ; 3:3, s. 178-182
-
Journal article (peer-reviewed)abstract
- In 44 consecutive patients with systemic sclerosis (SSc), plasma concentrations of von Willebrand factor (vWf) were higher than those of the vWf propeptide, but the propeptide showed less variability within patient subgroups. Higher values of the propeptide were observed in patients with early pulmonary involvement. A closer correlation of the propeptide than of vWf to biochemical markers of activity was also evident. Our results suggest that the propeptide, despite a shorter circulating half-time and lower plasma concentrations than vWf, is more useful in the assessment of disease activity in SSc.
|
|
| 26. |
|
|
| 27. |
- Wildt, Marie, et al.
(author)
-
Assessment of capillary density in systemic sclerosis with three different capillaroscopic methods
- 2012
-
In: Clinical and Experimental Rheumatology. - 1593-098X. ; 30:2, s. 50-54
-
Journal article (peer-reviewed)abstract
- Objectives: Capillary abnormalities, such as the enlargement and/or disappearance of capillary loops, occur early in the majority of patients with systemic sclerosis (SSc). The aim of this study was to compare three capillaroscopic methods of determining the capillary density in patients with SSc. Methods: Two of the three methods involved stereo-zoom microscopy at a magnification of 20 times, used either for direct counting, or with a camera and imaging software for determination of the capillary density on coded images. The third method was computerised nailfold video capillaroscopy with 300 x magnification using coded images. The capillary density (loops/mm) was determined on the fourth finger of the non-dominant hand with all three methods in 40 patients, 32 with limited cutaneous SSc (lcSSc) and 8 with diffuse cutaneous SSc (dcSSc), and in 21 healthy control subjects. Results: The median values of capillary density assessed with the three methods were: 4.3, 5.4 and 6.1 loops/mm in lcSSc patients, 4.5, 5.0 and 6.3 loops/mm in dcSSc patients, and 7.0, 7.0 and 6.9 loops/mm in the controls. Capillary density was thus lower in lcSSc and dcSSc patients than in the controls according to all three methods. Agreement between the three methods was good in the controls. In patients, direct counting resulted in lower values than in the two computer-based methods. Conclusion: Assessment of capillary density with three different methods showed good agreement between methods. All methods could differentiate between SSc patients and controls.
|
|
| 28. |
- Wildt, Marie, et al.
(author)
-
Simple counting of nailfold capillary density in suspected systemic sclerosis - 9 years' experience.
- 2007
-
In: Scandinavian Journal of Rheumatology. - : Informa UK Limited. - 1502-7732 .- 0300-9742. ; 36:6, s. 452-457
-
Journal article (peer-reviewed)abstract
- Objectives: Capillary damage is a characteristic feature of systemic sclerosis (SSc). This work aimed to explore the potential clinical value of simple microscopic counting of capillary density. Methods: In 325 patients admitted because of a clinical suspicion of SSc and in 80 healthy controls, nailfold capillary microscopy (NCM) was performed using a stereo-zoom microscope in 20x magnification and with a transparent ruler in one of the eyepieces. Capillaries were counted within 3 mm in the centre of the nailfold in eight fingers. Results: Capillary density (loops/mm) was decreased in patients with diffuse cutaneous SSc [median 4.7 (range 2.2-7.3)], limited cutaneous SSc [4.9 (2.0-7.3)], earlySSc [4.7 (2.8-7.3)], and preSSc [5.9 (4.3-8.2)] compared to healthy controls [7.2 (5.8-9.0)]. Patients with morphea and with primary Raynaud's phenomenon had normal numbers of capillaries [7.0 (6.2-7.2) and 7.0 (5.3-8.7), respectively]. In only 21/325 (6%) patients was it not possible to count the capillaries because of insufficient transparency of the skin. There was no discrepancy in capillary density based on counts of two or eight fingers. When 43 patients were reassessed after 1 to 4 years, there was no difference between the two assessments. Conclusion: Determination of capillary density by direct microscopy counts, a simple, inexpensive and rapid method, helps to identify patients with SSc, early in the disease course and in patients with very limited skin involvement.
|
|
| 29. |
- Wildt, Marie, et al.
(author)
-
Treatment with mycophenolate mofetil is associated with improved nailfold vasculature in systemic sclerosis
-
In: Rheumatology (Oxford, England). - 1462-0332.
-
Journal article (peer-reviewed)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.
|
|
| 30. |
- Wuttge, Dirk, et al.
(author)
-
Interleukin-15 attenuates transforming growth factor-beta1-induced myofibroblast differentiation in human fetal lung fibroblasts.
- 2010
-
In: European Cytokine Network. - 1952-4005. ; 21, s. 165-176
-
Journal article (peer-reviewed)abstract
- ObjectiveFibroproliferative diseases are common causes of morbidity and mortality. Interleukin-15 (IL-15) is a pleiotropic cytokine with multiple effects on cells of the immune system. Although IL-15 is also expressed in mesenchymal cells, its effects on the development of fibrosis are unknown. We have previously described an association between serum IL-15 levels and the extent of pulmonary fibrosis in the connective tissue disease systemic sclerosis, suggesting that IL-15 may have profibrotic effects. To test this hypothesis, we studied the effects of IL-15 on myofibroblast differentiation, an in vitro model of fibrosis development.MethodsWe used human fetal lung fibroblasts for the cytokine stimulation. As a marker of myofibroblast differentiation, alpha-smooth muscle actin (alpha-SMA) was analyzed by western blot and quantitative real-time PCR. The well-known profibrotic cytokine, transforming growth factor-beta1(TGF-beta1), was used for comparison, and TGF-beta signaling paths were also studied.ResultsIL-15 did not induce alpha-SMA expression, a marker for myofibroblast differentiation. Unexpectedly, IL-15 counteracted TGF-beta1-mediated alpha-SMA expression. Moreover, TGF-beta1-induced expression of collagen, fibronectin and connective tissue growth factor was attenuated by addition of IL-15. There was no effect of IL-15 on early events in the TGF-beta signaling cascades.ConclusionIL-15 has anti-fibrotic properties that, speculatively however, may be insufficient in systemic sclerosis.
|
|
| 31. |
- Wuttge, Dirk M., et al.
(author)
-
Circulating plasma microRNAs in systemic sclerosis-associated pulmonary arterial hypertension
- 2022
-
In: Rheumatology (United Kingdom). - : Oxford University Press (OUP). - 1462-0324 .- 1462-0332. ; 61:1, s. 309-318
-
Journal article (peer-reviewed)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.
|
|
| 32. |
- Wuttge, Dirk, et al.
(author)
-
Serum IL-15 in patients with early systemic sclerosis: a potential novel marker of lung disease
- 2007
-
In: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6362 .- 1478-6354. ; 9:5
-
Journal article (peer-reviewed)abstract
- ABSTRACT: The pathogenesis of systemic sclerosis (SSc) is characterized by autoimmunity, vasculopathy and fibrosis. IL-15 is a pleiotropic cytokine that has impact on immune, vascular and connective tissue cells. We therefore investigated IL-15 in the circulation of patients with early SSc and explored possible associations of serum IL-15 with vasculopathy and fibrosis. Serum levels of IL-15 were analysed in 63 consecutive patients with SSc of disease duration less than 4 years and without disease-modifying treatment. Thirty-three age-matched healthy control individuals were enrolled. Serum IL-15 levels were increased in the sera of SSc patients compared with that of healthy control individuals (P < 0.01). Serum IL-15 levels correlated with impaired lung function, assessed both by the vital capacity (P < 0.05) and by the carbon monoxide diffusion capacity (P < 0.05). The association between IL-15 and the vital capacity remained after multiple linear regression analysis. Patients with intermediate serum IL-15 levels had a higher prevalence of increased systolic pulmonary pressure compared with patients with either low or high serum IL-15 levels (P < 0.05). Moreover, increased serum IL-15 levels were associated with a reduced nailfold capillary density in multivariable logistic regression analysis (P < 0.01). Serum IL-15 levels also correlated inversely with the systolic blood pressure (P < 0.01). We conclude that IL-15 is associated with fibrotic as well as vascular lung disease and vasculopathy in early SSc. IL-15 may contribute to the pathogenesis of SSc. IL-15 could also be a candidate biomarker for pulmonary involvement and a target for therapy in SSc.
|
|
| 33. |
|
|
| 34. |
|
|
