OBJECTIVES:Fibrosis is the dominant hallmark of systemic sclerosis (SSc). Several mechanisms have been proposed to drive the disease process, but how these relate to skin fibrosis is poorly... Show moreOBJECTIVES:Fibrosis is the dominant hallmark of systemic sclerosis (SSc). Several mechanisms have been proposed to drive the disease process, but how these relate to skin fibrosis is poorly understood.METHODS:We performed a cross-sectional study on archival skin biopsies from 18 SSc patients and four controls. Dermal fibrosis and inflammatory cell infiltration were scored in HE and Masson’s Trichrome-stained sections. The presence of senescence was defined by P21 and/or P16 positivity in Ki-67 negative cells. Endothelial to mesenchymal transition (EndMT) was identified by co-localisation of CD31 and α-SMA in immunofluorescent double-stained sections, and by an enclosure of ERG positive endothelial cell nuclei by α-SMA stained cytoplasm in immunohistochemical double staining.RESULTS:The histological dermal fibrosis score of SSc skin biopsies was correlated with the modified Rodnan skin score (rho 0.55, p=0.042). Staining for markers of cellular senescence on fibroblasts was correlated with fibrosis score, inflammatory score, and CCN2 staining on fibroblasts. Moreover, EndMT was more abundant in skin from patients with SSc (p<0.01) but did not differ between groups with different fibrosis severity. The frequency of these EndMT features increased with the abundance of senescence markers and CCN2 on fibroblasts and dermal inflammation.CONCLUSIONS:EndMT and fibroblast senescence were more abundant in skin biopsies from SSc patients. This finding indicates that both senescence and EndMT are involved in the pathway leading to skin fibrosis and might be valuable biomarkers and/or possible targets for novel therapeutic interventions. Show less
Liem, S.I.E.; Ciaffi, J.; Leeuwen, N.M. van; Boonstra, M.; Ahmed, S.; Voorde, L.J.J. van de; ... ; Vries-Bouwstra, J. de 2023
Background: Since 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study... Show moreBackground: Since 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study evaluated whether early recognition of SSc has improved over time and whether disease characteristics and survival has changed over time. Methods: 643 SSc patients fulfilling American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria were included and categorised into three groups based on cohort-entry year: (1) 2010-2013 (n=229 (36%)), (2) 2014-2017 (n=207 (32%)) and (3) 2018-2021 (n=207 (32%)). Variables including disease duration, interstitial lung disease (ILD), digital ulcers (DU), diffuse cutaneous SSc (dcSSc), antitopoisomerase (ATA) and anticentromere (ACA) antibodies, and survival from disease onset were compared between cohort-entry groups, including analyses stratified for sex and autoantibodies. Results: Over time, duration between onset of disease symptoms and cohort entry decreased in males and females, but was always longer in females than in males.The proportion of patients presenting with DU decreased, especially in ACA+SSc patients. Almost no ACA+ patients presented with ILD, while in ATA+ patients this proportion was 25% in 2010-2013 and decreased to 19% in 2018-2021. A reduction in patients presenting with clinically meaningful ILD and dcSSc was observed.Overall 8-year survival for males was 59% (95% CI 40% to 73%) and for females 89% (95% CI 82% to 93%). Eight-year survival showed a trend for improvement over time, and was always worse in males. Conclusion: We observed a decrease in disease duration in Leiden CCISS cohort at cohort entry, possibly indicating more timely diagnosis of SSc. This could provide opportunities for early interventions. While symptom duration at presentation is longer in females, mortality is consistently higher in males, underlining the urge for sex-specific treatment and follow-up. Show less
Liem, S.I.E.; Ciaffi, J.; Leeuwen, N.M. van; Boonstra, M.; Ahmed, S.; Voorde, L.J.J. van de; ... ; Vries-Bouwstra, J. de 2023
Background Since 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study... Show moreBackground Since 2009, Dutch patients with a confirmed diagnosis/suspicion of systemic sclerosis (SSc) can be referred to the Leiden Combined Care in Systemic Sclerosis (CCISS) cohort. This study evaluated whether early recognition of SSc has improved over time and whether disease characteristics and survival has changed over time.Methods 643 SSc patients fulfilling American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria were included and categorised into three groups based on cohort-entry year: (1) 2010–2013 (n=229 (36%)), (2) 2014–2017 (n=207 (32%)) and (3) 2018–2021 (n=207 (32%)). Variables including disease duration, interstitial lung disease (ILD), digital ulcers (DU), diffuse cutaneous SSc (dcSSc), antitopoisomerase (ATA) and anticentromere (ACA) antibodies, and survival from disease onset were compared between cohort-entry groups, including analyses stratified for sex and autoantibodies.Results Over time, duration between onset of disease symptoms and cohort entry decreased in males and females, but was always longer in females than in males.The proportion of patients presenting with DU decreased, especially in ACA+SSc patients. Almost no ACA+ patients presented with ILD, while in ATA+ patients this proportion was 25% in 2010–2013 and decreased to 19% in 2018–2021. A reduction in patients presenting with clinically meaningful ILD and dcSSc was observed.Overall 8-year survival for males was 59% (95% CI 40% to 73%) and for females 89% (95% CI 82% to 93%). Eight-year survival showed a trend for improvement over time, and was always worse in males.Conclusion We observed a decrease in disease duration in Leiden CCISS cohort at cohort entry, possibly indicating more timely diagnosis of SSc. This could provide opportunities for early interventions. While symptom duration at presentation is longer in females, mortality is consistently higher in males, underlining the urge for sex-specific treatment and follow-up. Show less
Pulmonary function tests (PFTs) play an important role in screening and following-up pulmonary involvement in systemic sclerosis (SSc). However, some patients are not able to perform PFTs due to... Show morePulmonary function tests (PFTs) play an important role in screening and following-up pulmonary involvement in systemic sclerosis (SSc). However, some patients are not able to perform PFTs due to contraindications. In addition, it is unclear how lung function is affected by changes in lung structure in SSc. Therefore, this study aims to explore the potential of automatically estimating PFT results from chest CT scans of SSc patients and how different regions influence the estimation of PFTs. Deep regression networks were developed with transfer learning to estimate PFTs from 316 SSc patients. Segmented lungs and vessels were used to mask the CT images to train the network with different inputs: from entire CT scan, lungs-only to vessels-only. The network trained on entire CT scans with transfer learning achieved an ICC of 0.71, 0.76, 0.80, and 0.81 for the estimation of DLCO, FEV1, FVC and TLC, respectively. The performance of the networks gradually decreased when trained on data from lungs-only and vessels-only. Regression attention maps showed that regions close to large vessels were highlighted more than other regions, and occasionally regions outside the lungs were highlighted. These experiments show that apart from the lungs and large vessels, other regions contribute to PFT estimation. In addition, adding manually designed biomarkers increased the correlation (R) from 0.75, 0.74, 0.82, and 0.83 to 0.81, 0.83, 0.88, and 0.90, respectively. This suggests that that manually designed imaging biomarkers can still contribute to explaining the relation between lung function and structure. Show less
Boonstra, M.; Ciaffi, J.; Noordhoek, D.C.; Liem, S.I.E.; Beaart-van de Voorde, L.J.J.; Bijnen, S.T.A. van; ... ; Vries-Bouwstra, J.K. de 2022
Objective: Haematopoietic stem cell transplantation (HSCT) is a treatment option for patients with severe systemic sclerosis (SSc), but the efficacy of the procedure in remodelling the nailfold... Show moreObjective: Haematopoietic stem cell transplantation (HSCT) is a treatment option for patients with severe systemic sclerosis (SSc), but the efficacy of the procedure in remodelling the nailfold microvascular array is largely unknown. Therefore, this study aimed to evaluate the effect of HSCT on microangiopathy assessed through nailfold capillaroscopy (NC) and to compare the results with findings in patients receiving conventional immunosuppression. Methods: We included SSc patients with severe SSc and whose pre-and post-treatment NC images were available. Findings in patients treated with HSCT were compared with patients not treated with HSCT. Images were scored by two independent observers blinded for clinical data and treatment history. Capillary pattern was determined and semiquantitative scores from 0 (no changes) to 3 (> 66% alterations per millimetre) were used to quantify the degree of specific microvascular characteristics. Changes in severity of microangiopathy between baseline and post-treatment were compared between groups. Results: Images of 18 HSCT patients and 21 controls were scored. From baseline to follow-up, 33% of HSCT patients showed improvement from scleroderma pattern to normal NC, compared to 6% of controls (p=0.15). Pre-to post-treatment differences in semiquantitative scores showed significant improvement in HSCT patients compared to controls regarding capillary loss (-0.5 vs. 0.0, p < 0.05) and disorganisation (-0.8 vs. 0.0, p < 0.05). Conclusion: The degree of microangiopathy improved significantly in severe SSc patients treated with HSCT compared with patients receiving conventional immunosuppressive therapy. Show less
Positron emission tomography (PET) is a promising technique to improve the assessment of systemic sclerosis associated interstitial lung disease (SSc-ILD). This technique could be of particular... Show morePositron emission tomography (PET) is a promising technique to improve the assessment of systemic sclerosis associated interstitial lung disease (SSc-ILD). This technique could be of particular value in patients with severe diffuse cutaneous SSc (dcSSc) that are possibly eligible for autologous hematopoietic stem cell transplantation (aHSCT). aHSCT is a potentially effective therapy for patients with severe dcSSc and ILD, leading to stabilization or improvement of lung function. However, there is a high need to improve patient selection, which includes (1) the selection of patients with rapidly progressive ILD for early rather than last-resort aHSCT (2) the prediction of treatment response on ILD and (3) the understanding of the mechanism(s) of action of aHSCT in the lungs. As previous studies with F-18-FDG PET in SSc-ILD and other forms of ILD have demonstrated its potential value in predicting disease progression and reactivity to anti-inflammatory treatment, we discuss the potential benefit of using this technique in patients with early severe dcSSc and ILD in the context of aHSCT. In addition, we discuss the potential value of other PET tracers in the assessment of ILD and understanding the mechanisms of action of aHSCT in the lung. Finally, we provide several suggestions for future research. Show less
Liem, S.I.E.; Vlieland, T.P.M.V.; Ende, C.H. van de; Dittmar, S.; Schriemer, M.R.; Bodegom-Vos, L. van; ... ; Vries-Bouwstra, J.K. de 2022
Objective: This study aimed to develop recommendations for communication and postgraduate education regarding primary care physical therapy for systemic sclerosis (SSc) patients. Methods: A virtual... Show moreObjective: This study aimed to develop recommendations for communication and postgraduate education regarding primary care physical therapy for systemic sclerosis (SSc) patients. Methods: A virtual Nominal Group Technique was used with tasks forces for communication (n = 18) and education = 21). Both included rheumatologists, physical therapists (PTs) in primary, secondary or tertiary care, rheumatology nurses, advanced nurse practictioners and patient representatives. Three online meetings were organised for each task force to discuss (1) current bottlenecks; (2) potential solutions; and (3) the resulting draft recommendations. After the final adjustments, participants rated their level of agreement with each recommendation on a scale from 0 (not at all agree) to 100 (totally agree), using an online questionnaire. Results: 19 and 34 recommendations were formulated for communication and education, respectively. For communication the main recommendations concerned the provision of an overview of primary care physical therapists with expertise in rheumatic and musculoskeletal diseases to patients and rheumatologists, the inclusion of the indication by the rheumatologist in the referral to the physical therapist and low-threshold communication with the rheumatologist in case of questions or concerns of the physical therapist. For postgraduate education three types of "on demand" educational offerings were recommended with varying levels of content and duration, to match the competencies and preferences of individual primary care physical therapists. Conclusion: Using a systematic qualitative approach, two multi-stakeholder task forces developed practical recommendations for primary care physical therapists' communication with hospital-based care providers and postgraduate education regarding the treatment of SSc patients. Show less
IntroductionRight ventricular (RV) function is of particular importance in systemic sclerosis (SSc), since common SSc complications, such as interstitial lung disease and pulmonary hypertension may... Show moreIntroductionRight ventricular (RV) function is of particular importance in systemic sclerosis (SSc), since common SSc complications, such as interstitial lung disease and pulmonary hypertension may affect RV afterload. Cardiovascular magnetic resonance (CMR) is the gold standard for measuring RV function. CMR-derived RV and right atrial (RA) strain is a promising tool to detect subtle changes in RV function, and might have incremental value, however, prognostic data is lacking. Therefore, the aim of this study was to evaluate the prognostic value of RA and RV strain in SSc. MethodsIn this retrospective study, performed at two Dutch hospitals, consecutive SSc patients who underwent CMR were included. RV longitudinal strain (LS) and RA strain were measured. Unadjusted cox proportional hazard regression analysis and likelihood ratio tests were used to evaluate the association and incremental value of strain parameters with all-cause mortality. ResultsA total of 100 patients (median age 54 [46-64] years, 42% male) were included. Twenty-four patients (24%) died during a follow-up of 3.1 [1.8-5.2] years. RA reservoir [Hazard Ratio (HR) = 0.95, 95% CI 0.91-0.99, p = 0.009] and conduit strain (HR = 0.93, 95% CI 0.88-0.98, p = 0.008) were univariable predictors of all-cause mortality, while RV LS and RA booster strain were not. RA conduit strain proved to be of incremental value to sex, atrial fibrillation, NYHA class, RA maximum volume indexed, and late gadolinium enhancement (p < 0.05 for all). ConclusionRA reservoir and conduit strain are predictors of all-cause mortality in SSc patients, whereas RV LS is not. In addition, RA conduit strain showed incremental prognostic value to all evaluated clinical and imaging parameters. Therefore, RA conduit strain may be a useful prognostic marker in SSc patients. Show less
Systemic sclerosis (SSc) is a chronic autoimmune disorder with unknown triggering factors, and complex pathophysiologic links which lead to fibrosis of skin and internal organs, including the heart... Show moreSystemic sclerosis (SSc) is a chronic autoimmune disorder with unknown triggering factors, and complex pathophysiologic links which lead to fibrosis of skin and internal organs, including the heart, lungs, and gut. However, more than 100 years after the first description of cardiac disease in SSc, sclerodermic cardiomyopathy (SScCmp) is an underrecognized, occult disease with important adverse long-term prognosis. Laboratory tests, electrocardiography (ECG) and cardiovascular multimodality imaging techniques (transthoracic 2D and 3D echocardiography, cardiac magnetic resonance (CMR), and novel imaging techniques, including myocardial deformation analysis) provide new insights into the cardiac abnormalities in patients with SSc. This state-of-the-art review aims to stratify all the cardiac investigations needed to diagnose and follow-up the SScCmp, and discusses the epidemiology, risk factors and pathophysiology of this important cause of morbidity of the SSc patient. Show less
Abouyahya, I.; Liem, S.I.E.; Amoura, Z.; Fonseca, J.E.; Chaigne, B.; Cutolo, M.; ... ; Vries-Bouwstra, J.K. de 2022
Objective. Health-Related Quality of Life (HRQoL) in adult patients with mixed connective tissue disease (MCTD) has not been described so far. Therefore, we performed an explorative study to... Show moreObjective. Health-Related Quality of Life (HRQoL) in adult patients with mixed connective tissue disease (MCTD) has not been described so far. Therefore, we performed an explorative study to evaluate HRQoL in MCTD patients.Methods. MCTD patients fulfilling the Kahn criteria and participating in the prospective follow-up cohort for MCTD of the Leiden University Medical Center were included; and matched to systemic sclerosis (SSc) patients based on age, sex and disease duration. Data on disease characteristics and HRQoL (SF36 and EQ-5D) were collected annually. HRQoL was compared between MCTD and SSc patients at baseline. Factors associated with HRQoL in MCTD were identified using linear regression and change in HRQoL over 3 years using linear mixed models.Results. Thirty-four MCTD patients (121 visits) and 102 SSc patients (424 visits) were included. At baseline, MCTD patients presented with interstitial lung disease, cardiac involvement, synovitis and myositis more frequently compared to SSc patients, while use of immunosuppressive medication was less frequent. In both groups, mean SF36 scores were lower than in the general Dutch population. The SF36 subscore "general health perception" was impacted most in both groups (MCTD: 38.5 [SD:7.0], SSc: 39.9 [SD:8.9]). During follow-up, SF36 scores improved in MCTD patients, while EQ5DNL remained stable. No specific characteristics were identified that associated with baseline HRQoL or change in HRQol over time.Conclusion. Like in SSc, HRQoL in MCTD is significantly impaired, especially the general health perception of patients. Evaluation in larger prospective cohorts is needed to identify characteristics that impact HRQol most. Show less
Objectives In SSc patients, disease specific determinants that influence health-related quality of life (HRQoL) over time have not been described. We aim to, in patients with SSc, (i) evaluate if... Show moreObjectives In SSc patients, disease specific determinants that influence health-related quality of life (HRQoL) over time have not been described. We aim to, in patients with SSc, (i) evaluate if and how HRQoL changes over time, and (ii) assess how different SSc domains and functional impairments contribute to changes in HRQoL over time. Methods All SSc patients from the Leiden SSc cohort were included; patients with disease duration <24 months were classified as incident cases. HRQoL was assessed prospectively on an annual basis using the EQ-5D and the SF36. To assess baseline associations between clinical characteristics and HRQoL, linear regressions were performed. To identify possible associations between SSc characteristics and HRQoL change over time, linear mixed models were performed in both incident and prevalent cases. Results In total, 492 SSc patients were included (n = 202 incident cases), with a median follow-up duration of 3.4 years. At baseline, presence of organ involvement was independently associated with a worse SF36 physical component score and lower EQ-5D score. Over time, gastrointestinal symptoms, Raynaud and digital ulcers were independently associated with deterioration of HRQoL in both incident and prevalent cases. In prevalent cases, pulmonary arterial hypertension (PAH) was associated with a decrease in HRQoL over time. Worse functioning as measured by six-min walking distance, mouth-opening, finger-to-palm distance and grip-strength contributed significantly to deterioration of HRQoL over time. Conclusion In SSc, key clinical burdens that contribute to worsening of HRQoL over time include digital ulcers, Raynaud and gastrointestinal involvement. In addition, PAH is a significant burden in prevalent disease. Show less
Acosta-Herrera, M.; Kerick, M.; Lopez-Isac, E.; Assassi, S.; Beretta, L.; Simeon-Aznar, C.P.; ... ; Australian Scleroderma Inter 2021
Objective The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we... Show moreObjective The greatest genetic effect reported for systemic sclerosis (SSc) lies in the major histocompatibility complex (MHC) locus. Leveraging the largest SSc genome-wide association study, we aimed to fine-map this region to identify novel human leucocyte antigen (HLA) genetic variants associated with SSc susceptibility and its main clinical and serological subtypes. Methods 9095 patients with SSc and 17 584 controls genome-wide genotyped were used to impute and test single-nucleotide polymorphisms (SNPs) across the MHC, classical HLA alleles and their composite amino acid residues. Additionally, patients were stratified according to their clinical and serological status, namely, limited cutaneous systemic sclerosis (lcSSc), diffuse cutaneous systemic sclerosis (dcSSc), anticentromere (ACA), antitopoisomerase (ATA) and anti-RNApolIII autoantibodies (ARA). Results Sequential conditional analyses showed nine SNPs, nine classical alleles and seven amino acids that modelled the observed associations with SSc. This confirmed previously reported associations with HLA-DRB1*11:04 and HLA-DPB1*13:01, and revealed a novel association of HLA-B*08:01. Stratified analyses showed specific associations of HLA-DQA1*02:01 with lcSSc, and an exclusive association of HLA-DQA1*05:01 with dcSSc. Similarly, private associations were detected in HLA-DRB1*08:01 and confirmed the previously reported association of HLA-DRB1*07:01 with ACA-positive patients, as opposed to the HLA-DPA1*02:01 and HLA-DQB1*03:01 alleles associated with ATA presentation. Conclusions This study confirms the contribution of HLA class II and reveals a novel association of HLA class I with SSc, suggesting novel pathways of disease pathogenesis. Furthermore, we describe specific HLA associations with SSc clinical and serological subtypes that could serve as biomarkers of disease severity and progression. Show less
Objectives. In SSc patients, disease specific determinants that influence health-related quality of life (HRQoL) over time have not been described. We aim to, in patients with SSc, (i) evaluate if... Show moreObjectives. In SSc patients, disease specific determinants that influence health-related quality of life (HRQoL) over time have not been described. We aim to, in patients with SSc, (i) evaluate if and how HRQoL changes over time, and (ii) assess how different SSc domains and functional impairments contribute to changes in HRQoL over time.Methods. All SSc patients from the Leiden SSc cohort were included; patients with disease duration <24 months were classified as incident cases. HRQoL was assessed prospectively on an annual basis using the EQ-5D and the SF36. To assess baseline associations between clinical characteristics and HRQoL, linear regressions were performed. To identify possible associations between SSc characteristics and HRQoL change over time, linear mixed models were performed in both incident and prevalent cases.Results. In total, 492 SSc patients were included (n = 202 incident cases), with a median follow-up duration of 3.4 years. At baseline, presence of organ involvement was independently associated with a worse SF36 physical component score and lower EQ-5D score. Over time, gastrointestinal symptoms, Raynaud and digital ulcers were independently associated with deterioration of HRQoL in both incident and prevalent cases. In prevalent cases, pulmonary arterial hypertension (PAH) was associated with a decrease in HRQoL over time. Worse functioning as measured by six-min walking distance, mouth-opening, finger-to-palm distance and grip-strength contributed significantly to deterioration of HRQoL over time.Conclusion. In SSc, key clinical burdens that contribute to worsening of HRQoL over time include digital ulcers, Raynaud and gastrointestinal involvement. In addition, PAH is a significant burden in prevalent disease. Show less
Objective. Autoreactive antibody responses, including the use of several isotypes of autoantibodies, have been shown to be associated with clinical outcome in several rheumatic autoimmune diseases.... Show moreObjective. Autoreactive antibody responses, including the use of several isotypes of autoantibodies, have been shown to be associated with clinical outcome in several rheumatic autoimmune diseases. The goals of this study were to evaluate whether (1) anticentrornere antibody (ACA)- and antitopoisomerase antibody (ATA)-specific isotype expression, and (2) organ involvement are associated with the degree of microangiopathy in systemic sclerosis (SSc).Methods. ACA and MA IgG, IgM, and IgA levels were measured in baseline serum samples of ACA IgG-positive (+) and ATA IgG+ patients with SSc. The degree of microangiopathy was determined based on nailfold videocapillaroscopy (NVC) images collected at the same point in time. Logistic regression analyses with autoantibodies, clinical characteristics, isotype expression, and ACA and ATA IgG, IgM, and IgA levels as independent variables, and NVC pattern as the dependent variable were performed.Results. In 164 patients, isotype levels and degree of microangiopathy were evaluated. Logistic regression confirmed the association of the degree of microangiopathy with the presence of digital ulcers (OR 3.07, 95% CI 1.43-6.60), interstitial lung disease (OR 3.41, 95% CI 1.11-10.61), and pulmonary arterial hypertension (OR 5.58, 95% CI 2.05-17.81). ATA positivity was associated with more severe microangiopathy (OR 2.09, 95% CI 1.05-4.13). Patients who expressed solely ACA IgG showed a trend towards less severe microangiopathy compared to patients also expressing ACA IgM and/or IgA. Levels of ACA IgG and ATA IgM were found to be associated with microangiopathy severity.Conclusion. We observed an association between ACA and ATA responses and the degree of microangiopathy in SSc. These findings might indicate that the breadth of the autoimmune response, as reflected by autoantibody production and microvascular damage, interacts in the pathophysiology of SSc. Show less
Khedoe, P.; Marges, E.; Hiemstra, P.; Ninaber, M.; Geelhoed, M. 2020
Systemic sclerosis (SSc) is an autoimmune connective tissue disease, characterized by immune dysregulation and progressive fibrosis. Interstitial lung disease (ILD) is the most common cause of... Show moreSystemic sclerosis (SSc) is an autoimmune connective tissue disease, characterized by immune dysregulation and progressive fibrosis. Interstitial lung disease (ILD) is the most common cause of death among SSc patients and there are currently very limited approved disease-modifying treatment options for systemic sclerosis-related interstitial lung disease (SSc-ILD). The mechanisms underlying pulmonary fibrosis in SSc-ILD are not completely unraveled, and knowledge on fibrotic processes has been acquired mostly from studies in idiopathic pulmonary fibrosis (IPF). The incomplete knowledge of SSc-ILD pathogenesis partly explains the limited options for disease-modifying therapy for SSc-ILD. Fibrosis in IPF appears to be related to aberrant repair following injury, but whether this also holds for SSc-ILD is less evident. Furthermore, immune dysregulation appears to contribute to pro-fibrotic responses in SSc-ILD, perhaps more than in IPF. In addition, SSc-ILD patient heterogeneity complicates the understanding of the underlying mechanisms of disease development, and more importantly, limits correct clinical diagnosis and treatment effectivity. Therefore, there is an unmet need for patient-relevant (in vitro) models to examine patient-specific disease pathogenesis, predict disease progression, screen appropriate treatment regimens and identify new targets for treatment. Technological advances inin vitropatient-relevant disease modeling, including (human induced pluripotent stem cell (hiPSC)-derived) lung epithelial cells, organoids and organ-on-chip technology offer a platform that has the potential to contribute to unravel the underlying mechanisms of SSc-ILD development. Combining these models with state-of-the-art analysis platforms, including (single cell) RNA sequencing and (imaging) mass cytometry, may help to delineate pathogenic mechanisms and define new treatment targets of SSc-ILD. Show less
Spierings, J.; Ende, C.H.M. van den; Schriemer, R.M.; Moens, H.J.B.; Bijl, E.A. van der; Bonte-Mineur, F.; ... ; ARCH Study Grp 2020
Objectives. To gain insight into SSc patients' perspective on quality of care and to survey their preferred quality indicators.Methods. An online questionnaire about healthcare setting, perceived... Show moreObjectives. To gain insight into SSc patients' perspective on quality of care and to survey their preferred quality indicators.Methods. An online questionnaire about healthcare setting, perceived quality of care (CQ index) and quality indicators, was sent to 2093 patients from 13 Dutch hospitals.Results. Six hundred and fifty patients (mean age 59 years, 75% women, 32% limited cutaneous SSc, 20% diffuse cutaneous SSc) completed the questionnaire. Mean time to diagnosis was 4.3 years (s.d. 6.9) and was longer in women compared with men (4.8 (s.d. 7.3) vs 2.5 (s.d. 5.0) years). Treatment took place in a SSc expert centre for 58%, regional centre for 29% or in both for 39% of patients. Thirteen percent of patients was not aware of whether their hospital was specialized in SSc. The perceived quality of care was rated with a mean score of 3.2 (s.d. 0.5) (range 1.0-4.0). There were no relevant differences between expert and regional centres. The three prioritized process indicators were: good patient-physician interaction (80%), structural multidisciplinary collaboration (46%) and receiving treatment according to SSc guidelines (44%). Absence of disease progression (66%), organ involvement (33%) and digital ulcers (27%) were the three highest rated outcome indicators.Conclusion. The perceived quality of care evaluated in our study was fair to good. No differences between expert and regional centres were observed. Our prioritized process and outcome indicators can be added to indicators suggested by SSc experts in earlier studies and can be used to evaluate the quality of care in SSc. Show less
In this thesis, we developed methods focusing on quantifying pulmonary vascular diseases and assessing treatment effects, based on CT images. A lung vessel segmentation method was proposed in... Show moreIn this thesis, we developed methods focusing on quantifying pulmonary vascular diseases and assessing treatment effects, based on CT images. A lung vessel segmentation method was proposed in Chapter 2, as accurately extracting lung vessels is an essentialstep for pulmonary vessel analysis. An automatic method for pulmonary vessel quantification was developed in Chapter 3, where two imaging biomarkers were proposed for quantifying the vascular morphology. In Chapter 4, the relation between these imaging biomarkers and pulmonary function were investigated in a selected SSc patient group, who had reductions in gas transfer but did not have fibrosis. The densitometry changes in pulmonary vasculature and parenchyma were studied by comparing CTPA scans before and after treatment for CTEPH patients treated with BPA, in Chapter 5. A vascular tree matching method was proposed for matching pulmonaryvasculature trees, for quantifying changes in vascular morphology for CTEPH patients in Chapter 6. Show less
Leeuwen, N.M. van; Boonstra, M.; Huizinga, T.W.J.; Kaptein, A.A.; Vries-Bouwstra, J.K. de 2020
Objectives: This study explores illness perceptions, risk perceptions and degree of worry in patients with recently diagnosed systemic sclerosis (SSc). Specifically, it aims to answer whether and... Show moreObjectives: This study explores illness perceptions, risk perceptions and degree of worry in patients with recently diagnosed systemic sclerosis (SSc). Specifically, it aims to answer whether and how early diagnosis in a stage that disease is relatively mild can impact patients' lives, and if and how disease severity associates with illness perceptions and risk perception.Methods: Patients with a diagnosis of SSc <2 years were invited to participate in a focus group discussion for in-depth exploration of illness perceptions, risk perceptions and worry. In addition, illness perceptions, risk perceptions and worries were evaluated with the use of questionnaires. To explore how patients perceive SSc, we asked them to draw their disease. Physician global assessment of disease severity was used to measure disease severity. Associations between disease severity, illness/risk perceptions, drawings and elements of the focus group were assessed.Results: We observed three dimensions of illness perception as most relevant for patients: personal control, concern and consequences. Patients with SSc experienced many symptoms and felt low personal control. Concerns about the future were often mentioned, and the majority of patients scored high on the worry questionnaire. None of the patients was preoccupied with prognosis or death. All drawings illustrate the impact of SSc on daily life and psychological well-being. Illness perceptions were highly variable between patients and did not associate with disease severity.Conclusion: This study showed that a diagnosis of early SSc had a significant impact on patients' lives, also in the absence of severe disease complications. Show less
Objective. To investigate whether systemic sclerosis (SSc) patients exposed to active tobacco smoke exhibit a different autoantibody profile or are at higher risk for severe microangiopathy... Show moreObjective. To investigate whether systemic sclerosis (SSc) patients exposed to active tobacco smoke exhibit a different autoantibody profile or are at higher risk for severe microangiopathy compared to never-smokers, and to assess differences between men and women.Methods. We performed an exploratory observational study in a cohort of SSc patients fulfilling the 2013 ACR/EULAR classification criteria. According to the smoking habit, patients were categorised as ever-smokers or never-smokers. Microvascular damage was assessed at baseline using nailfold videocapillaroscopy. The presence of SSc-specific autoantibodies was investigated.Results. The studied population was composed of 361 patients (279 women, 82 men). Of these, 208 (58%) were ever-smokers and 153 (42%) were never-smokers. Anti-centromere, anti-topoisomerase I (ATA) and anti-RNA polymerase III antibodies were found, respectively, in 90 (43%), 41 (20%), and 11 (5%) ever-smokers, and in 66 (43%), 40 (26%) and 5 (3%) never-smokers (all p>0.05). Scleroderma patterns early, active and late were present respectively in 12%, 44% and 21% of ever-smokers, and in 9%, 48%, and 29% of never-smokers (all p>0.05). In multivariable logistic regression, being a never-smoker was significantly associated with ATA positivity (OR 1.77, 95% CI 1.04-2.99, p=0.034). In the gender-based sub-cohorts, 36 (27%) female patients who never smoked were ATA positive, compared to 16 (11%) ever-smoking women (p<0.001).Conclusion. We observed a significant association between smoking history and positivity of ATA and we outlined the idea of a different effect of smoking on autoantibody expression between men and women. Show less
