Publications by authors named "Oliver Distler"

390 Publications

Computed tomography-based radiomics decodes prognostic and molecular differences in interstitial lung disease related to systemic sclerosis.

Eur Respir J 2021 Oct 14. Epub 2021 Oct 14.

Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

Background: Radiomic features calculated from routine medical images show great potential for personalized medicine in cancer. Patients with systemic sclerosis (SSc), a rare, multi-organ autoimmune disorder, have a similarly poor prognosis due to interstitial lung disease (ILD).

Objectives: To explore computed tomography (CT)-based high-dimensional image analysis (radiomics) for disease characterisation, risk stratification, and relaying information on lung pathophysiology in SSc-ILD.

Methods: We investigated two independent, prospectively followed SSc-ILD cohorts (Zurich, derivation cohort, n=90; Oslo, validation cohort, n=66). For every subject, we defined 1'355 robust radiomic features from standard-of-care CT images. We performed unsupervised clustering to identify and characterize imaging-based patient clusters. A clinically applicable prognostic quantitative radiomic risk score (qRISSc) for progression-free survival was derived from radiomic profiles using supervised analysis. The biological basis of qRISSc was assessed in a cross-species approach by correlation with lung proteomics, histological and gene expression data derived from mice with bleomycin-induced lung fibrosis.

Results: Radiomic profiling identified two clinically and prognostically distinct SSc-ILD patient clusters. To evaluate the clinical applicability, we derived and externally validated a binary, quantitative radiomic risk score composed of 26 features, qRISSc, that accurately predicted progression-free survival and significantly improved upon clinical risk stratification parameters in multivariable Cox regression analyses in the pooled cohorts. A high qRISSc score, which identifies patients at risk for progression, was reverse translatable from human to experimental ILD and correlated with fibrotic pathway activation.

Conclusions: Radiomics-based risk stratification using routine CT images provides complementary phenotypic, clinical and prognostic information significantly impacting clinical decision-making in SSc-ILD.
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http://dx.doi.org/10.1183/13993003.04503-2020DOI Listing
October 2021

Editorial: Precision Medicine in Chronic Inflammation.

Front Immunol 2021 23;12:770462. Epub 2021 Sep 23.

Department of Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.

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http://dx.doi.org/10.3389/fimmu.2021.770462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8495129PMC
September 2021

Nintedanib in patients with systemic sclerosis-associated interstitial lung disease: subgroup analyses by autoantibody status and skin score.

Arthritis Rheumatol 2021 Sep 12. Epub 2021 Sep 12.

Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Objective: We used data from the SENSCIS trial to assess the effects of nintedanib versus placebo in subgroups of patients with SSc-ILD based on characteristics associated with progression of SSc-ILD in previous studies.

Methods: Patients with SSc-ILD were randomized to receive nintedanib or placebo, stratified by anti-topoisomerase I antibody (ATA) status. We assessed the rate of decline in forced vital capacity (FVC) (mL/year) over 52 weeks in subgroups by baseline ATA status, modified Rodnan skin score (mRSS) (<18 versus ≥18), and SSc subtype (limited cutaneous SSc [lcSSc] versus diffuse cutaneous SSc [dcSSc]).

Results: At baseline, of 576 patients treated, 60.8% were ATA-positive, 51.9% had dcSSc, and 77.5% of 574 patients with mRSS data available had mRSS <18. The effect of nintedanib versus placebo on reducing the rate of decline in FVC (mL/year) was numerically more pronounced in patients who were ATA-negative (difference: 57.2 [95% CI -3.5, 118.0]) than ATA-positive (difference: 29.9 [-19.1, 78.8]), in patients who had mRSS ≥18 (difference: 88.7 [7.7, 169.8]) than mRSS <18 at baseline (difference: 26.4 [-16.8, 69.6]), and in patients with dcSSc (difference: 56.6 [3.2, 110.0]) than lcSSc (difference: 25.3 [-28.9, 79.6]), but exploratory interaction P values did not indicate heterogeneity in the effect of nintedanib versus placebo between these subgroups (P > 0.05 for all).

Conclusion: In patients with SSc-ILD, no heterogeneity was detected in the treatment effect of nintedanib in reducing the annual rate of decline in FVC across subgroups based on ATA status, mRSS, and SSc subtype.
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http://dx.doi.org/10.1002/art.41965DOI Listing
September 2021

Elevated Fibronectin Levels in Profibrotic CD14 Monocytes and CD14 Macrophages in Systemic Sclerosis.

Front Immunol 2021 24;12:642891. Epub 2021 Aug 24.

Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: Systemic sclerosis (SSc) is an autoimmune disease characterized by overproduction of extracellular matrix (ECM) and multiorgan fibrosis. Animal studies pointed to bone marrow-derived cells as a potential source of pathological ECM-producing cells in immunofibrotic disorders. So far, involvement of monocytes and macrophages in the fibrogenesis of SSc remains poorly understood.

Methods And Results: Immunohistochemistry analysis showed accumulation of CD14 monocytes in the collagen-rich areas, as well as increased amount of alpha smooth muscle actin (αSMA)-positive fibroblasts, CD68 and mannose-R macrophages in the heart and lungs of SSc patients. The full genome transcriptomics analyses of CD14 blood monocytes revealed dysregulation in cytoskeleton rearrangement, ECM remodeling, including elevated (gene encoding fibronectin) expression and TGF-β signalling pathway in SSc patients. In addition, single cell RNA sequencing analysis of tissue-resident CD14 pulmonary macrophages demonstrated activated profibrotic signature with the elevated expression in SSc patients with interstitial lung disease. Peripheral blood CD14 monocytes obtained from either healthy subjects or SSc patients exposed to profibrotic treatment with profibrotic cytokines TGF-β, IL-4, IL-10, and IL-13 increased production of type I collagen, fibronectin, and αSMA. In addition, CD14 monocytes co-cultured with dermal fibroblasts obtained from SSc patients or healthy individuals acquired a spindle shape and further enhanced production of profibrotic markers. Pharmacological blockade of the TGF-β signalling pathway with SD208 (TGF-β receptor type I inhibitor), SIS3 (Smad3 inhibitor) or (5Z)-7-oxozeaenol (TGF-β-activated kinase 1 inhibitor) ameliorated fibronectin levels and type I collagen secretion.

Conclusions: Our findings identified activated profibrotic signature with elevated production of profibrotic fibronectin in CD14 monocytes and CD14 pulmonary macrophages in SSc and highlighted the capability of CD14 monocytes to acquire a profibrotic phenotype. Taking together, tissue-infiltrating CD14 monocytes/macrophages can be considered as ECM producers in SSc pathogenesis.
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http://dx.doi.org/10.3389/fimmu.2021.642891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421541PMC
September 2021

Patient and healthcare professional eHealth literacy and needs for systemic sclerosis support: a mixed methods study.

RMD Open 2021 09;7(3)

Institute of Nursing Science, Department Public Health, Faculty of Medicine, University of Basel, Basel, Switzerland

Objectives: We engaged patients with systemic sclerosis (SSc) and healthcare professionals to assess electronic health (eHealth) literacy and needs relating to web-based support using internet-based information and communication technologies (ICT).

Methods: We employed an explanatory sequential mixed methods design. First, we conducted a cross-sectional survey in patients (n=101) and professionals (n=47). Next, we conducted three focus groups with patients, family members and professionals (n=17).

Results: Of patients, 89.1% used ICT at least weekly for private communication. Patients reported relatively high comprehension of eHealth information ([Formula: see text] =6.7, 95% CI: 6.2 to 7.3, range 1-10), yet were less confident evaluating information reliability ([Formula: see text] =5.8, 95% CI: 5.1 to 6.4) and finding eHealth apps ([Formula: see text] =4.8, 95% CI: 4.2 to 5.4). Patients and professionals reported little experience with web-based self-management support. Focus groups revealed 'considering non-ICT-accessible groups and 'fitting patients' and professionals' technology as crucial for acceptability. In relation to understanding/appraising eHealth, participants highlighted that general SSc information is not tailored to individual's disease course. Recommendations included 'providing timely, understandable and safe information and 'empowering end-users in ICT and health decision-making skills. Professionals expressed concerns about lacking resources. Patients were concerned about data security and person-centredness. Key eHealth drivers included 'addressing end-user perceptions and 'putting people at the centre of technology.

Conclusions: Patients and professionals need education/training to support uptake of eHealth resources. Key elements include guiding patients to timely/reliable information and using eHealth to optimise patient-provider communication. Design that is responsive to end-users' needs and considers individuals with limited eHealth literacy and/or ICT access appears to be critical for acceptability.
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http://dx.doi.org/10.1136/rmdopen-2021-001783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8413951PMC
September 2021

Patients with systemic sclerosis show phenotypic and functional defects in neutrophils.

Allergy 2021 Sep 1. Epub 2021 Sep 1.

Department of Immunology, University Hospital Zurich, Zurich, Switzerland.

Background: Systemic sclerosis (SSc) is a multiorgan autoimmune disease characterized by inflammation, vascular modification, and progressive fibrosis of the skin and several visceral organs. Innate and adaptive immune cells, including myeloid, B and T cells, are believed to be central to the pathogenesis of SSc. However, the role and functional state of neutrophil granulocytes (neutrophils) are ill-defined in SSc.

Methods: We performed a prospective study of neutrophils freshly isolated from SSc patients and healthy donors (HD) by measuring in these neutrophils (i) functional cell surface markers, including CD16, CD62L, CD66b, CD66c, CXCR1, CXCR2, and CXCR4; (ii) cytokine-activated intracellular signal transducer and activator of transcription (STAT) pathways, such as phosphorylated STAT3 (pSTAT3), pSTAT5, and pSTAT6; (iii) production of neutrophil extracellular traps (NET) and intracellular myeloperoxidase (MPO); and (iv) phagocytosis of bacteria by the neutrophils.

Results: Neutrophils of SSc patients expressed lower CD16 and CD62L and higher pSTAT3 and pSTAT6 compared to HD. Moreover, neutrophils of SSc patients lacked CXCR1 and CXCR2, the receptors responding to the potent neutrophil chemoattractant CXCL8. Neutrophils of SSc patients were also deficient in MPO levels, NET formation, and phagocytosis of bacteria.

Conclusions: Neutrophils of patients with SSc display several functional defects affecting cell migration, NET formation, and phagocytosis of bacteria.
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http://dx.doi.org/10.1111/all.15073DOI Listing
September 2021

Functional genomics atlas of synovial fibroblasts defining rheumatoid arthritis heritability.

Genome Biol 2021 08 25;22(1):247. Epub 2021 Aug 25.

Department of Rheumatology, Center of Experimental Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Background: Genome-wide association studies have reported more than 100 risk loci for rheumatoid arthritis (RA). These loci are shown to be enriched in immune cell-specific enhancers, but the analysis so far has excluded stromal cells, such as synovial fibroblasts (FLS), despite their crucial involvement in the pathogenesis of RA. Here we integrate DNA architecture, 3D chromatin interactions, DNA accessibility, and gene expression in FLS, B cells, and T cells with genetic fine mapping of RA loci.

Results: We identify putative causal variants, enhancers, genes, and cell types for 30-60% of RA loci and demonstrate that FLS account for up to 24% of RA heritability. TNF stimulation of FLS alters the organization of topologically associating domains, chromatin state, and the expression of putative causal genes such as TNFAIP3 and IFNAR1. Several putative causal genes constitute RA-relevant functional networks in FLS with roles in cellular proliferation and activation. Finally, we demonstrate that risk variants can have joint-specific effects on target gene expression in RA FLS, which may contribute to the development of the characteristic pattern of joint involvement in RA.

Conclusion: Overall, our research provides the first direct evidence for a causal role of FLS in the genetic susceptibility for RA accounting for up to a quarter of RA heritability.
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http://dx.doi.org/10.1186/s13059-021-02460-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8385949PMC
August 2021

A rare disease patient-reported outcome measure: revision and validation of the German version of the Systemic Sclerosis Quality of Life Questionnaire (SScQoL) using the Rasch model.

Orphanet J Rare Dis 2021 08 9;16(1):356. Epub 2021 Aug 9.

Institute of Nursing Science (INS), Department Public Health (DPH), Faculty of Medicine, University of Basel, Basel, Switzerland.

Background: Rare disease patient-reported outcome measures (PROMs) require linguistic adaptation to overcome the challenge of geographically dispersed patient populations. Importantly, PROMs such as health-related quality of life (HRQoL) should accurately capture responses to patient-identified concerns. The Systemic Sclerosis Quality of Life Questionnaire (SScQoL) is a 29-item tool validated in six languages. Previous evaluation of the German version revealed problems with dichotomous responses. This study aimed to revise the German SScQoL, extend the response structure, and evaluate content and construct validity, reliability and unidimensionality.

Methods: The instrument validation study involved revising the German SScQoL response structure, cognitive debriefing with patients and validation using Rasch analysis. The revised SScQoL was completed by Swiss-German-speaking patients with SSc within the Swiss MANagement Of Systemic Sclerosis (MANOSS) study. Rasch analysis was employed to test the validity, reliability and unidimensionality of the revised instrument.

Results: Based on cognitive debriefing with patients (n = 6) dichotomous items were extended to a polytomous 4-point response structure. A total of 78 patients completed the revised SScQoL. Initial analysis of the 29 items suggested the scale lacked fit to the model (χ = 51.224, df = 29, p = 0.007). Grouping items into five domains resulted in an adequate fit to the Rasch model (χ = 5.343, df = 5, p = 0.376) and unidimensionality (proportion of significant independent t tests: 0.045, 95% CI 0.016-0.114). Overall, the scale was well targeted, had high internal consistency (Person Separation Index, PSI = 0.931) and worked consistently in patients with different demographic and clinical characteristics.

Conclusions: The revised German SScQoL has a 4-point response structure and is a valid, reliable measure. Rasch analysis is useful for validating continuous response structure of quality of life measures. Further evaluation of measurement equivalence with other German-speaking cultures is required for multinational comparisons and data pooling.
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http://dx.doi.org/10.1186/s13023-021-01944-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351336PMC
August 2021

An open-label study to evaluate biomarkers and safety in systemic sclerosis patients treated with paquinimod.

Arthritis Res Ther 2021 07 31;23(1):204. Epub 2021 Jul 31.

Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

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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http://dx.doi.org/10.1186/s13075-021-02573-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8325221PMC
July 2021

Wound Image Quality From a Mobile Health Tool for Home-Based Chronic Wound Management With Real-Time Quality Feedback: Randomized Feasibility Study.

JMIR Mhealth Uhealth 2021 07 30;9(7):e26149. Epub 2021 Jul 30.

Mobile Health Systems Lab, Institute of Robotics and Intelligent Systems, Department of Health Sciences and Technology, ETH Zurich, Zurich, Switzerland.

Background: Travel to clinics for chronic wound management is burdensome to patients. Remote assessment and management of wounds using mobile and telehealth approaches can reduce this burden and improve patient outcomes. An essential step in wound documentation is the capture of wound images, but poor image quality can have a negative influence on the reliability of the assessment. To date, no study has investigated the quality of remotely acquired wound images and whether these are suitable for wound self-management and telemedical interpretation of wound status.

Objective: Our goal was to develop a mobile health (mHealth) tool for the remote self-assessment of digital ulcers (DUs) in patients with systemic sclerosis (SSc). We aimed to define and validate objective measures for assessing the image quality, evaluate whether an automated feedback feature based on real-time assessment of image quality improves the overall quality of acquired wound images, and evaluate the feasibility of deploying the mHealth tool for home-based chronic wound self-monitoring by patients with SSc.

Methods: We developed an mHealth tool composed of a wound imaging and management app, a custom color reference sticker, and a smartphone holder. We introduced 2 objective image quality parameters based on the sharpness and presence of the color checker to assess the quality of the image during acquisition and enable a quality feedback mechanism in an advanced version of the app. We randomly assigned patients with SSc and DU to the 2 device groups (basic and feedback) to self-document their DU at home over 8 weeks. The color checker detection ratio (CCDR) and color checker sharpness (CCS) were compared between the 2 groups. We evaluated the feasibility of the mHealth tool by analyzing the usability feedback from questionnaires, user behavior and timings, and the overall quality of the wound images.

Results: A total of 21 patients were enrolled, of which 15 patients were included in the image quality analysis. The average CCDR was 0.96 (191/199) in the feedback group and 0.86 (158/183) in the basic group. The feedback group showed significantly higher (P<.001) CCS compared to the basic group. The usability questionnaire results showed that the majority of patients were satisfied with the tool, but could benefit from disease-specific adaptations. The median assessment duration was <50 seconds in all patients, indicating the mHealth tool was efficient to use and could be integrated into the daily routine of patients.

Conclusions: We developed an mHealth tool that enables patients with SSc to acquire good-quality DU images and demonstrated that it is feasible to deploy such an app in this patient group. The feedback mechanism improved the overall image quality. The introduced technical solutions consist of a further step towards reliable and trustworthy digital health for home-based self-management of wounds.
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http://dx.doi.org/10.2196/26149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8367165PMC
July 2021

A randomised, double-blind, placebo-controlled phase 3 study of lenabasum in diffuse cutaneous systemic sclerosis: RESOLVE-1 design and rationale.

Clin Exp Rheumatol 2021 Jul-Aug;39 Suppl 131(4):124-133. Epub 2021 Jul 21.

UCL Centre for Rheumatology and Connective Tissue Diseases, Royal Free Campus, University College London, UK.

Objectives: The multi-systemic, heterogenous nature of diffuse cutaneous systemic sclerosis (dcSSc) presents challenges in designing clinical studies that can demonstrate a treatment effect on overall disease burden. We describe the design of the first Phase 3 study in dcSSc patients where the American College of Rheumatology (ACR) Combined Response Index in diffuse cutaneous Systemic Sclerosis (CRISS) score was chosen prospectively as the primary outcome. The CRISS measures key clinical disease parameters and patient-reported outcomes (PROs).

Methods: RESOLVE-1 is a Phase 3, randomised, double-blind, placebo-controlled trial of dcSSc patients evaluating the efficacy and safety of lenabasum. Patients ≥18 years of age with dc-SSc and disease duration ≤6 years were eligible. Patients could continue stable background therapy for dcSSc, including stable immunosuppressive therapies. They were randomised to lenabasum 5 or 20 mg twice daily or placebo. The primary efficacy outcome was the mean change from baseline to 52 weeks in the ACR CRISS score.

Results: The study enrolled 365 patients over 1.5 years at 77 sites in 13 countries in North America, Europe, Israel, and Asia-Pacific, with the last patient first visit on May 1, 2019.

Conclusions: RESOLVE-1 is the first Phase 3 interventional study to date in dcSSc to prospectively use the ACR CRISS as the primary efficacy outcome. Eligibility criteria allowed background therapy as might occur in clinical practice. This approach also facilitated timely patient enrolment. RESOLVE-1 provides a novel study design that may be used for future Phase 3 dcSSc studies to assess the holistic efficacy of therapy.
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August 2021

Diagnostic measures for patients with systemic sclerosis-associated myopathy.

Clin Exp Rheumatol 2021 Jul-Aug;39 Suppl 131(4):85-93. Epub 2021 Jul 15.

Department of Rheumatology and Immunology, University Hospital Bern, Switzerland.

Objectives: To evaluate the clinico-serological profile and to assess diagnostic parameters of myopathy in patients with systemic sclerosis (SSc)-associated myopathy.

Methods: We explored the profiles of SSc-myopathy patients and matched non-myopathy SSc patients as well as different diagnostic measures for muscle affection. Additionally, the muscle performance of SSc-myopathy patients, assessed by the Manual Muscle Test for 8 muscle groups (MMT-8) and the Functional Index-2 (FI-2), was compared with that of patients with primary myositis.

Results: In SSc-myopathy patients, the following features occurred significantly more often even after Bonferroni correction for multiple comparisons: immunosuppressive treatment (56.0% vs. 24.1%; p=0.0003), elevated levels of creatine kinase (CK) (48.3% vs. 5.3%, p<0.0001), anti-PM-Scl antibodies (30.4% vs. 4%, p=0.00048), and absence of RNA Polymerase III antibodies (7.3% vs. 28.3%, p<0.0001). The MMT-8 showed a mild muscle weakness in SSc-myopathy as well as in primary myositis patients with similar age and sex. Muscle endurance tested by the FI-2 was generally compromised in both cohorts, yet the distribution pattern of affected muscle groups differed between the two cohorts.

Conclusions: We confirmed previously described clinic-serological characteristics of SSc-myopathy patients. Our study suggests that autoantibody profile and CK levels may be helpful in establishing the diagnosis of SSc-myopathy. Whole-body MRI might be more accurate to capture the disease extent than MRI of selected muscle groups. Functional muscle tests validated for primary myositis did not perform well for the assessment of muscle function in patients with SSc-myopathy. Both, potential confounders such as skin, joint, and cardiovascular involvement as well as lack of sensitivity might have negatively affected the test performance in this population.
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August 2021

Individual functions of the histone acetyl transferases CBP and p300 in regulating the inflammatory response of synovial fibroblasts.

J Autoimmun 2021 Sep 23;123:102709. Epub 2021 Jul 23.

Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland; Department of BioMedical Research, University of Bern, Bern, Switzerland; Department of Rheumatology and Immunology, University Hospital Bern, Bern, Switzerland. Electronic address:

Chromatin remodeling, and a persistent histone 3 lysine 27 acetylation (H3K27ac) in particular, are associated with a sustained inflammatory response of synovial fibroblasts (SF) in rheumatoid arthritis (RA). Here we investigated individual functions of the writers of H3K27ac marks, the homologues histone acetyl transferases (HAT) CBP and p300, in controlling the constitutive and inflammatory gene expression in RA SF. We applied a silencing strategy, followed by RNA-sequencing and pathway analysis, complemented with the treatment of SF with inhibitors targeting the HAT (C646) or bromo domains (I-CBP) of CBP and p300. We showed that CBP and p300 undertook overlapping and, in particular at gene levels, distinct regulatory functions in SF. p300 is the major HAT for H3K27ac in SF and regulated more diverse pathways than CBP. Whereas both factors regulated genes associated with extracellular matrix remodeling, adhesion and proliferation, p300 specifically controlled developmental genes associated with limb development. Silencing of CBP specifically down regulated the TNF-induced expression of interferon-signature genes. In contrast, silencing of p300 resulted in anti- and pro-inflammatory effects. Integration of data sets derived from RNA-sequencing and chromatin immunoprecipitation sequencing for H3K27ac revealed that changes in gene expression after CBP or p300 silencing could be only partially explained by changes in levels of H3K27ac. Inhibition of CBP/p300 using HAT and bromo domain inhibitors strongly mirrored effects obtained by silencing of p300, including anti- and pro-inflammatory effects, indicating that such inhibitors are not sufficient to be used as anti-inflammatory drugs.
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http://dx.doi.org/10.1016/j.jaut.2021.102709DOI Listing
September 2021

The burden of systemic sclerosis in Switzerland - the Swiss systemic sclerosis EUSTAR cohort.

Swiss Med Wkly 2021 07 14;151:w20528. Epub 2021 Jul 14.

Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland.

Objectives: Characteristics of Swiss patients with systemic sclerosis have not been described so far. The aim of the current study was to identify unmet needs in comparison with other European countries that could inform specific interventions to improve the care of systemic sclerosis patients.

Methods: We analysed Swiss and other European systemic sclerosis patients registered in European Scleroderma Trials And Research (EUSTAR) and the Very Early Diagnosis Of Systemic Sclerosis (VEDOSS) cohort. Demographics, clinical profiles, organ involvement and survival of established, early/mild and very early / very mild systemic sclerosis patients were described and compared between the cohorts.

Results: We included 679 Swiss and 8793 European systemic sclerosis patients in the analysis. Over 95% of patients in both cohorts were Caucasian, disease subsets were similar, and no age difference was found. The Swiss cohort had more male patients (25% vs 16% European, p = 0.005) and higher prevalence of early/mild and very early / very mild patients (26.1 vs 8.5% European and 14.9% vs 6.7% European, respectively, both p <0.0001). Disease duration in established systemic sclerosis patients at first presentation was numerically shorter but not significant in the Swiss cohort: 5.0 years (1–12) Swiss vs 6.0 years (2–12) years European, p = 0.055). Despite the earlier referral of Swiss patients to systemic sclerosis expert centres, they showed evidence of more severe disease, particularly in the limited cutaneous systemic sclerosis subset, but no differences in overall survival on longitudinal follow-up were observed.

Conclusion: This is the first report of the national Swiss EUSTAR cohort. It identifies earlier referral to systemic sclerosis expert centres, before major organ damage occurs, and when outcome can still be modified, as a priority to improve care of patients with systemic sclerosis.
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http://dx.doi.org/10.4414/smw.2021.20528DOI Listing
July 2021

Engrailed 1 coordinates cytoskeletal reorganization to induce myofibroblast differentiation.

J Exp Med 2021 Sep 14;218(9). Epub 2021 Jul 14.

Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg and University Hospital Erlangen, Erlangen, Germany.

Transforming growth factor-β (TGFβ) is a key mediator of fibroblast activation in fibrotic diseases, including systemic sclerosis. Here we show that Engrailed 1 (EN1) is reexpressed in multiple fibroblast subpopulations in the skin of SSc patients. We characterize EN1 as a molecular amplifier of TGFβ signaling in myofibroblast differentiation: TGFβ induces EN1 expression in a SMAD3-dependent manner, and in turn, EN1 mediates the profibrotic effects of TGFβ. RNA sequencing demonstrates that EN1 induces a profibrotic gene expression profile functionally related to cytoskeleton organization and ROCK activation. EN1 regulates gene expression by modulating the activity of SP1 and other SP transcription factors, as confirmed by ChIP-seq experiments for EN1 and SP1. Functional experiments confirm the coordinating role of EN1 on ROCK activity and the reorganization of cytoskeleton during myofibroblast differentiation, in both standard fibroblast culture systems and in vitro skin models. Consistently, mice with fibroblast-specific knockout of En1 demonstrate impaired fibroblast-to-myofibroblast transition and are partially protected from experimental skin fibrosis.
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http://dx.doi.org/10.1084/jem.20201916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8288503PMC
September 2021

Dysregulated Expression of Arterial MicroRNAs and Their Target Gene Networks in Temporal Arteries of Treatment-Naïve Patients with Giant Cell Arteritis.

Int J Mol Sci 2021 Jun 17;22(12). Epub 2021 Jun 17.

Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, 8952 Schlieren, Switzerland.

In this study, we explored expression of microRNA (miR), miR-target genes and matrix remodelling molecules in temporal artery biopsies (TABs) from treatment-naïve patients with giant cell arteritis (GCA, = 41) and integrated these analyses with clinical, laboratory, ultrasound and histological manifestations of GCA. NonGCA patients ( = 4) served as controls. GCA TABs exhibited deregulated expression of several miRs (miR-21-5p, -145-5p, -146a-5p, -146b-5p, -155-5p, 424-3p, -424-5p, -503-5p), putative miR-target genes (, , , , ) and matrix remodelling factors (, , , ) with key roles in Toll-like receptor signaling, mechanotransduction and extracellular matrix biology. MiR-424-3p, -503-5p, , and were identified as new deregulated molecular factors in GCA TABs. Quantities of miR-146a-5p, , , , and were particularly high in histologically positive GCA TABs with occluded temporal artery lumen. MiR-424-5p expression in TABs and the presence of facial or carotid arteritis on ultrasound were associated with vision disturbances in GCA patients. Correlative analysis of miR-mRNA quantities demonstrated a highly interrelated expression network of deregulated miRs and mRNAs in temporal arteries and identified as a candidate target gene of deregulated miR-21-5p, -146a-5p and -155-5p network in GCA TABs. Meanwhile, arterial miR and mRNA expression did not correlate with constitutive symptoms and signs of GCA, elevated markers of systemic inflammation nor sonographic characteristics of GCA. Our study provides new insights into GCA pathophysiology and uncovers new candidate biomarkers of vision impairment in GCA.
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http://dx.doi.org/10.3390/ijms22126520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234166PMC
June 2021

Safety and efficacy of faecal microbiota transplantation by Anaerobic Cultivated Human Intestinal Microbiome (ACHIM) in patients with systemic sclerosis: study protocol for the randomised controlled phase II ReSScue trial.

BMJ Open 2021 06 24;11(6):e048541. Epub 2021 Jun 24.

Department of Rheumatology, Oslo University Hospital, Oslo, Norway.

Introduction: In the multisystem inflammatory disorder systemic sclerosis (SSc), gastrointestinal tract (GIT) affliction is highly prevalent. There are no known disease modifying therapies and the negative impact is substantial. Aiming for a new therapeutic principle, and inspired by recent work showing associations between gut microbiota changes and GIT symptoms in SSc, we performed a pilot study on faecal microbiota transplantation (FMT) with the single-donor bacterial culture 'Anaerobic Cultivated Human Intestinal Microbiome (ACHIM)'. Motivated by positive pilot study signals, we designed the ReSScue trial as a phase II multicentre, placebo-controlled, randomised 20-week trial to evaluate safety and efficacy on lower GIT symptoms of FMT by ACHIM in SSc.

Methods And Analyses: We aim to include 70 SSc participants with moderate to severe lower GIT symptoms, defined by the validated patient-reported University of California Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 2.0 questionnaire. The trial includes three parts. In part A1 (induction phase) lasting from week 0 to week 12, participants will be randomised 1:1 to repeat infusions of 30 mL ACHIM or placebo at week 0 and 2 by gastroduodenoscopy. In part A2, which is an 8-week subsequent maintenance phase, all study participants will receive 30 mL ACHIM at week 12 and followed until week 20 on continued blind. In part B, which will last until the last participant completes part A2, the participants will be followed through a maximum 16-week extended monitoring period, for longer-term data on safety and intervention effects. Primary endpoint is change from baseline to week 12 in UCLA GIT subscale scores of diarrhoea or bloating, depending on the worst symptom at baseline evaluated separately for each patient. Secondary endpoints are safety measures and changes in UCLA GIT scores (total, diarrhoea and bloating).

Ethics And Dissemination: This protocol was approved by the Northern Norwegian Committee for Medical Ethics. Study findings will be published.

Trial Registration Number: NCT04300426; Pre-results.

Protocol Version: V.3.1.
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http://dx.doi.org/10.1136/bmjopen-2020-048541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231046PMC
June 2021

Staphylococcus aureus impairs dermal fibroblast functions with deleterious effects on wound healing.

FASEB J 2021 07;35(7):e21695

Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, Zurich, Switzerland.

Chronic wounds are a major disease burden worldwide. The breach of the epithelial barrier facilitates transition of skin commensals to invasive facultative pathogens. Therefore, we investigated the potential effects of Staphylococcus aureus (SA) on dermal fibroblasts as key cells for tissue repair. In co-culture systems combining live or heat-killed SA with dermal fibroblasts derived from the BJ-5ta cell line, healthy individuals, and patients with systemic sclerosis, we assessed tissue repair including pro-inflammatory cytokines, matrix metalloproteases (MMPs), myofibroblast functions, and host defense responses. Only live SA induced the upregulation of IL-1β/-6/-8 and MMP1/3 as co-factors of tissue degradation. Additionally, the increased cell death reduced collagen production, proliferation, migration, and contractility, prerequisite mechanisms for wound closure. Intracellular SA triggered inflammatory and type I IFN responses via intracellular dsDNA sensor molecules and MyD88 and STING signaling pathways. In conclusion, live SA affected various key tissue repair functions of dermal fibroblasts from different sources to a similar extent. Thus, SA infection of dermal fibroblasts should be taken into account for future wound management strategies.
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http://dx.doi.org/10.1096/fj.201902836RDOI Listing
July 2021

Digital pitting scars are associated with a severe disease course and death in systemic sclerosis: a study from the EUSTAR cohort.

Rheumatology (Oxford) 2021 Jun 19. Epub 2021 Jun 19.

Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Florence, Italy.

Objective: Digital pitting scars (DPS) are frequent, but little studied in SSc to date.

Methods: An analysis of SSc patients enrolled in the EUSTAR database. Primary objectives were to 1) examine DPS prevalence, 2) whether DPS are associated with digital ulcers (DUs) and active digital ischaemia (DUs or gangrene), and 3) describe other associations with DPS including internal organ complications. Secondary objectives were whether DPS are associated with 1) functional impairment, 2) structural microvascular disease, 3) and mortality. Descriptive statistics and parametric/non-parametric tests were used. Binary logistic regression was used to examine the association between DPS and DUs, active digital ischaemia, and mortality.

Results: 9671 patients were included with reported DPS at any time point (n = 4924) or 'never' DPS (n = 4747). The majority (86.9%) were female and mean age was 55.7 years. DPS were associated with longer disease and Raynaud's duration (both P = <0.001). DPS were associated with interstitial lung disease, pulmonary hypertension, conduction blocks, telangiectases, calcinosis (all P = <0.001) and joint synovitis (P = <0.021). Patients were more likely to have more severe capillaroscopic abnormality and greater hand functional impairment. Multivariable logistic regression analyses showed that DPS were associated (OR) with DUs: 22.03 (19.51 to 24.87), active digital ischaemia: 6.30 (5.34 to 7.42), and death: 1.86 (1.48 to 2.36).

Conclusion: DPS are associated with a severe disease course including death. The impact of DPS on hand function and ischaemia is significant. The presence of DPS should alert the clinician to a poor prognosis and need to optimise the therapeutic strategy.
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http://dx.doi.org/10.1093/rheumatology/keab510DOI Listing
June 2021

Anti-centromere antibody levels and isotypes and the development of systemic sclerosis.

Arthritis Rheumatol 2021 May 27. Epub 2021 May 27.

Leiden University Medical Centre, Department of Rheumatology, Leiden, The Netherlands.

Objectives: Little is known on the disease course of very early systemic sclerosis (SSc). It is unknown whether anti-centromere antibody (ACA) isotype levels can serve as biomarkers for future SSc development and for organ involvement. We aim to evaluate whether ACA-IgG, -IgM and -IgA levels in ACA-IgG positive patients associate with disease severity and/or progression from very early SSc to definite SSc.

Methods: ACA-IgG positive patients with very early SSc and ACA-IgG positive patients fulfilling the 2013 ACR/EULAR criteria for SSc from five different cohorts were included. A diagnosis of very early SSc was based on the presence of ACA-IgG AND Raynaud and/or puffy fingers and/or abnormal nailfold capillaroscopy but not fulfilling the 2013 ACR/EULAR criteria. Multivariable regression analyses were performed to determine the association between baseline isotype levels and progression to SSc and organ involvement.

Results: Six hundred twenty-five ACA-IgG positive patients were included of whom 138 (22%) fulfilled very early SSc criteria and 487 (78%) had definite SSc. ACA-IgG (Odds Ratio (OR) 2.5 (1.8-3.7)) and ACA-IgM (OR 1.8 (1.3 -2.3)) levels were significantly higher in definite SSc patients. Of 115 very early SSc patients with follow-up, 48 (42%) progressed to definite SSc within five years. Progression to definite SSc was associated with higher ACA-IgG levels at baseline (OR 4.3 (1.7-10.7)).

Conclusion: ACA isotype levels might serve as a biomarker to identify very early SSc patients at risk for progression to definite SSc.
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http://dx.doi.org/10.1002/art.41814DOI Listing
May 2021

Representativeness of Systemic Sclerosis Patients in Interventional Randomized Trials: an analysis of the EUSTAR database.

Rheumatology (Oxford) 2021 May 14. Epub 2021 May 14.

Rheumatology Unit, Geneva University Hospitals and University of Geneva, Geneva, Switzerland.

Objective: To estimate the extent of and the reasons for ineligibility in randomized controlled trials (RCTs) of systemic sclerosis (SSc) patients included in the EUSTAR database, and to determine the association between patient's features and generalizability of study results.

Methods: We searched Clinicaltrials.gov for all records on interventional SSc-RCTs registered from January 2013 to January 2018. Two reviewers selected studies, and information on the main trial features were retrieved. Data from 8046 patients having a visit in the EUSTAR database since 2013 were used to check patient's eligibility. The proportion of potentially eligible patients per trial, and the risk factors for ineligibility were analyzed. Complete-, worst- and best-case analyses were performed.

Results: Of the 37 RCTs included, 43% were conducted in Europe, 35% were industry-funded, and 87% investigated pharmacological treatments. Ninety-one percent of 8046 patients included could have participated in at least one RCT. In complete-case analysis, the median [range] proportion of eligible patients having the main organ complication targeted by each study was 60% [10-100] in the overall sample of trials, ranging from 50% [32-79] for trials on skin fibrosis to 90% [34-77] for those targeting Raynaud's phenomenon. Among the criteria checked, treatment- and safety-related but not demographic were the main barriers to patient's recruitment. Older age, absence of Raynaud's phenomenon, and lower mRSS were independently associated with the failure to fulfill criteria for any of the included studies.

Conclusions: Patient's representativeness in SSc-RCTs is highly variable and is driven more by treatment- and safety-related rather than demographic criteria.
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http://dx.doi.org/10.1093/rheumatology/keab437DOI Listing
May 2021

Secondary attack rates from asymptomatic and symptomatic influenza virus shedders in hospitals: Results from the TransFLUas influenza transmission study.

Infect Control Hosp Epidemiol 2021 May 6:1-7. Epub 2021 May 6.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital and University of Zurich, Zurich, Switzerland.

Objective: Nosocomial transmission of influenza is a major concern for infection control. We aimed to dissect transmission dynamics of influenza, including asymptomatic transmission events, in acute care.

Design: Prospective surveillance study during 2 influenza seasons.

Setting: Tertiary-care hospital.

Participants: Volunteer sample of inpatients on medical wards and healthcare workers (HCWs).

Methods: Participants provided daily illness diaries and nasal swabs for influenza A and B detection and whole-genome sequencing for phylogenetic analyses. Contacts between study participants were tracked. Secondary influenza attack rates were calculated based on spatial and temporal proximity and phylogenetic evidence for transmission.

Results: In total, 152 HCWs and 542 inpatients were included; 16 HCWs (10.5%) and 19 inpatients (3.5%) tested positive for influenza on 109 study days. Study participants had symptoms of disease on most of the days they tested positive for influenza (83.1% and 91.9% for HCWs and inpatients, respectively). Also, 11(15.5%) of 71 influenza-positive swabs among HCWs and 3 (7.9%) of 38 influenza-positive swabs among inpatients were collected on days without symptoms; 2 (12.5%) of 16 HCWs and 2 (10.5%) of 19 inpatients remained fully asymptomatic. The secondary attack rate was low: we recorded 1 transmission event over 159 contact days (0.6%) that originated from a symptomatic case. No transmission event occurred in 61 monitored days of contacts with asymptomatic influenza-positive individuals.

Conclusions: Influenza in acute care is common, and individuals regularly shed influenza virus without harboring symptoms. Nevertheless, both symptomatic and asymptomatic transmission events proved rare. We suggest that healthcare-associated influenza prevention strategies that are based on preseason vaccination and barrier precautions for symptomatic individuals seem to be effective.
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http://dx.doi.org/10.1017/ice.2021.112DOI Listing
May 2021

Performance of the UCLA Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 instrument as a clinical decision aid in the routine clinical care of patients with systemic sclerosis.

Arthritis Res Ther 2021 04 22;23(1):125. Epub 2021 Apr 22.

Department of Rheumatology, University Hospital Zurich, University of Zurich, Gloriastrasse 25, 8091, Zurich, Switzerland.

Background And Objectives: The University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 2.0 (UCLA GIT 2.0) is validated to capture gastrointestinal (GI) tract morbidity in patients with systemic sclerosis (SSc). The aims of this study were to determine in a large SSc cohort if the UCLA GIT 2.0 is able to discriminate patients for whom a rheumatologist with experience in SSc would recommend an esophago-gastro-duodenoscopy (EGD), and if it could identify patients with endoscopically proven esophagitis or with any pathologic finding on EGD.

Methods: We selected patients fulfilling the ACR/EULAR 2013 criteria for SSc from our EUSTAR center having completed at least once the UCLA GIT 2.0 questionnaire, and we collected data on gastrointestinal symptoms and EGD from their medical charts. We analyzed by general linear mixed effect models several parameters, including UCLA GIT 2.0, considered as potentially associated with the indication of EGD, as well as with endoscopic esophagitis and any pathologic finding on EGD.

Results: We identified 346 patients (82.7% female, median age 63 years, median disease duration 10 years, 23% diffuse cutaneous SSc) satisfying the inclusion criteria, who completed UCLA GIT 2.0 questionnaires at 940 visits. EGD was recommended at 169 visits. In multivariable analysis, UCLA GIT 2.0 and some of its subscales (reflux, distention/bloating, social functioning) were associated with the indication of EGD. In 177 EGD performed in 145 patients, neither the total ULCA GIT 2.0 score nor any of its subscales were associated with endoscopic esophagitis, nor with any pathologic EGD findings.

Conclusions: In a real-life setting, the UCLA GIT 2.0 and its reflux subscale were able to discriminate patients with SSc who had an indication for EGD, but did not correlate with findings in EGD. We conclude that, while using the UCLA GIT 2.0 in the routine care of patients with SSc may help the rheumatologist to better understand the burden of GI symptoms in the individual patient, it should not be used as a stand-alone instrument to identify an indication of EGD.
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http://dx.doi.org/10.1186/s13075-021-02506-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8061014PMC
April 2021

The Hospital Anxiety and Depression Scale in patients with systemic sclerosis: a psychometric and factor analysis in a monocentric cohort.

Clin Exp Rheumatol 2021 Jul-Aug;39 Suppl 131(4):34-42. Epub 2021 Apr 21.

Department of Rheumatology, University Hospital Zurich, University of Zurich, Switzerland.

Objectives: To evaluate the feasibility, validity, reliability, and responsiveness of the Hospital Anxiety and Depression Scale (HADS) and to analyse its model structure in patients with systemic sclerosis (SSc).

Methods: In this study, 316 SSc patients were included; of these, 159 participated in the responsiveness analysis. Psychometric properties were tested in analogy to the Outcome Measures in Rheumatology (OMERACT) filter and an exploratory and confirmatory factor analysis was performed to examine the structure of HADS.

Results: The HADS showed adequate feasibility, validity, reliability, and responsiveness to clinically relevant worsening of the disease. For our population of SSc patients, the HADS model with two sub-scales, HADS-A and HADS-D, and a general scale HADS-S, measuring anxiety, depression, and distress, respectively, was most appropriate. The rates of anxiety, depression, mixed anxiety-depressive disorder (MADD) and distress identified by HADS were 32.2%, 25.9%, 18.5%, and 49.5%, respectively, in our cohort.

Conclusions: The psychometric properties of the HADS make it useful for screening in SSc, where anxiety, depression, MADD, and distress represent a significant burden to patients.
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August 2021

No evidence for an effect of working from home on neck pain and neck disability among Swiss office workers: Short-term impact of COVID-19.

Eur Spine J 2021 06 4;30(6):1699-1707. Epub 2021 Apr 4.

School of Health Professions, Institute of Health Sciences, Zurich University of Applied Sciences, Winterthur, Switzerland.

Purpose: The aim of this study was to investigate the effect of working from home on neck pain (NP) among office workers during the COVID-19 pandemic.

Methods: Participants from two Swiss organisations, aged 18-65 years and working from home during the lockdown (n = 69) were included. Baseline data collected in January 2020 before the lockdown (office work) were compared with follow-up data in April 2020 during lockdown (working from home). The primary outcome of NP was assessed with a measure of intensity and disability. Secondary outcomes were quality of workstation ergonomics, number of work breaks, and time spent working at the computer. Two linear mixed effects models were fitted to the data to estimate the change in NP.

Results: No clinically relevant change in the average NP intensity and neck disability was found between measurement time points. Each working hour at the computer increased NP intensity by 0.36 points (95% CI: 0.09 to 0.62) indicating strong evidence. No such effect was found for neck disability. Each work break taken reduced neck disability by 2.30 points (95% CI:  - 4.18 to  - 0.42, evidence). No such effect was found for NP intensity. There is very strong evidence that workstation ergonomics was poorer at home.

Conclusion: The number of work breaks and hours spent at the computer seem to have a greater effect on NP than the place of work (office, at home), measurement time point (before COVID-19, during lockdown) or the workstation ergonomics. Further research should investigate the effect of social and psychological factors.

Trial Registration: ClinicalTrials.gov, NCT04169646. Registered 15 November 2019-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04169646 .
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http://dx.doi.org/10.1007/s00586-021-06829-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019586PMC
June 2021

Assessment of Bone Mineral Density From a Computed Tomography Topogram of Photon-Counting Detector Computed Tomography-Effect of Phantom Size and Tube Voltage.

Invest Radiol 2021 10;56(10):614-620

From the Institute of Diagnostic and Interventional Radiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Purpose: The aim of this study was to assess the accuracy and impact of different sizes and tube voltages on bone mineral density (BMD) assessment using a computed tomography (CT) topogram acquired with photon-counting detector CT in an osteopenic ex vivo animal spine.

Materials And Methods: The lumbar back of a piglet was used to simulate osteopenia of the lumbar spine. Five fat layers (each with a thickness of 3 cm) were consecutively placed on top of the excised spine to emulate a total of 5 different sizes. Each size was repeatedly imaged on (A) a conventional dual-energy x-ray absorptiometry scanner as the reference standard, (B) a prototype photon-counting detector CT system at 120 kVp with energy thresholds at 20 and 70 keV, and (C) the same prototype system at 140 kVp with thresholds at 20 and 75 keV. Material-specific data were reconstructed from spectral topograms for B and C. Bone mineral density was measured for 3 lumbar vertebrae (L2-L4). A linear mixed-effects model was used to estimate the impact of vertebra, imaging setup, size, and their interaction term on BMD.

Results: The BMD of the lumbar spine corresponded to a T score in humans between -4.2 and -4.8, which is seen in osteoporosis. Averaged across the 3 vertebrae and 5 sizes, mean BMD was 0.56 ± 0.03, 0.55 ± 0.02, and 0.55 ± 0.02 g/cm2 for setup A, B, and C, respectively. There was no significant influence of imaging setup (P = 0.7), simulated size (P = 0.67), and their interaction term (both P > 0.2) on BMD. Bone mineral density decreased significantly from L2 to L4 for all 3 setups (all P < 0.0001). Bone mineral density was 0.59 ± 0.01, 0.57 ± 0.01, and 0.52 ± 0.02 g/cm2 for L2, L3, and L4, respectively, for setup A; 0.57 ± 0.02, 0.55 ± 0.01, and 0.53 ± 0.01 g/cm2 for setup B; and 0.57 ± 0.01, 0.55 ± 0.01, and 0.53 ± 0.01 g/cm2 for setup C.

Conclusion: A single CT topogram acquired on photon-counting detector CT with 2 energy thresholds enabled BMD quantification with similar accuracy compared with dual-energy x-ray absorptiometry over a range of simulated sizes and tube voltages in an osteopenic ex vivo animal spine.
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http://dx.doi.org/10.1097/RLI.0000000000000781DOI Listing
October 2021

Estimated glomerular filtration rate is a marker of mortality in the European Scleroderma Trials and Research Group (EUSTAR) database.

Rheumatology (Oxford) 2021 Mar 26. Epub 2021 Mar 26.

Department of Translational and Precision Medicine, Sapienza University of Rome, Italy.

Objectives: Study aim was to evaluate estimated glomerular filtration rate (eGFR), its association with clinical disease and its predictive ability with mortality in systemic sclerosis (SSc) patients from the European Scleroderma Trials and Research Group (EUSTAR) database.

Methods: SSc patients from the EUSTAR database with available items for calculation of eGFR at baseline visit and with a second follow-up visit were included. A cut-off of 60 ml/min was chosen for all SSc patients and 30 ml/min for scleroderma renal crisis (SRC). Cox regression and competing risk analysis were performed to evaluate the role of eGFR as predictive factor of mortality.

Results: 3650 SSc patients were included. Mean serum level of creatinine and eGFR were 0.8 mg/dl (IQR 0.6-0.9) and 86.6 ± 23.7 ml/min. The eGFR was significantly lower in patients with pulmonary hypertension. Overall survival (OS) was significantly reduced in SSc patients with eGFR <60 ml/min respect to patients with eGFR ≥ 60 ml/min [OS at five years 0.763 (CI 95%: 0.700-0.814) vs 0.903 (CI 95%: 0.883-0.919 p< 0.001)]. In multivariable analysis, OS was associate with male gender (p< 0.01), systolic pulmonary arterial pressure (sPAP) (p< 0.001) and eGFR (p< 0.001). Cumulative incidence of deaths due to SSc was associate with increased sPAP (p< 0.001) and reduced eGFR (p< 0.05). OS at five years of 53 SRC patients was not significantly different in SSc patients with eGFR > 30 ml/min or eGFR < 30 ml/min.

Conclusion: eGFR represents a predictive risk factor of overall survival in SSc. The eGFR is not a risk factor for death in SRC.
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http://dx.doi.org/10.1093/rheumatology/keab302DOI Listing
March 2021

Regulation of Monocyte Adhesion and Type I Interferon Signaling by CD52 in Patients With Systemic Sclerosis.

Arthritis Rheumatol 2021 09 31;73(9):1720-1730. Epub 2021 Jul 31.

University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Objective: Systemic sclerosis (SSc) is characterized by dysregulation of type I interferon (IFN) signaling. CD52 is known for its immunosuppressive functions in T cells. This study was undertaken to investigate the role of CD52 in monocyte adhesion and type I IFN signaling in patients with SSc.

Methods: Transcriptome profiles of circulating CD14+ monocytes from patients with limited cutaneous SSc (lcSSc), patients with diffuse cutaneous SSc (dcSSs), and healthy controls were analyzed by RNA sequencing. Levels of CD52, CD11b/integrin αΜ, and CD18/integrin β2 in whole blood were assessed by flow cytometry. CD52 expression was analyzed in relation to disease phenotype (early, lcSSc, dcSSc) and autoantibody profiles. The impact of overexpression, knockdown, and antibody blocking of CD52 was analyzed by gene and protein expression assays and functional assays.

Results: Pathway enrichment analysis indicated an increase in adhesion- and type I IFN-related genes in monocytes from SSc patients. These cells displayed up-regulated expression of CD11b/CD18, reduced expression of CD52, and enhanced adhesion to intercellular adhesion molecule 1 and endothelial cells. Changes in CD52 expression were consistent with the SSc subtypes, as well as with immunosuppressive treatments, autoantibody profiles, and monocyte adhesion properties in patients with SSc. Overexpression of CD52 led to decreased levels of CD18 and monocyte adhesion, while knockdown of CD52 increased monocyte adhesion. Experiments with the humanized anti-CD52 monoclonal antibody alemtuzumab in blood samples from healthy controls increased monocyte adhesion and CD11b/CD18 expression, and enhanced type I IFN responses. Monocytic CD52 expression was up-regulated by interleukin-4 (IL-4)/IL-13 via the STAT6 pathway, and was down-regulated by lipopolysaccharide and IFNs α, β, and γ in a JAK1 and histone deacetylase IIa (HDAC IIa)-dependent manner.

Conclusion: Down-regulation of the antiadhesion CD52 antigen in CD14+ monocytes represents a novel mechanism in the pathogenesis of SSc. Targeting of the IFN-HDAC-CD52 axis in monocytes might represent a new therapeutic option for patients with early SSc.
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http://dx.doi.org/10.1002/art.41737DOI Listing
September 2021

No Evidence for a Decrease in Physical Activity Among Swiss Office Workers During COVID-19: A Longitudinal Study.

Front Psychol 2021 11;12:620307. Epub 2021 Feb 11.

Institute of Psychology, University of Bern, Bern, Switzerland.

Purpose: The COVID-19 lockdown interrupted normal daily activities, which may have led to an increase in sedentary behavior (Castelnuovo et al., 2020). The aim of this study was to investigate the effect of the COVID-19 pandemic on the level of physical activity among Swiss office workers.

Methods: Office workers from two Swiss organizations, aged 18-65 years, were included. Baseline data from January 2020 before the COVID-19 pandemic became effective in Switzerland were compared with follow-up data during the lockdown phase in April 2020. Levels of physical activity were assessed using the International Physical Activity Questionnaire. Paired sample -tests or Wilcoxon signed-rank test were performed for statistical analysis.

Results: Data from 76 participants were analyzed. Fifty-four participants were female (71.1%). The mean age was 42.7 years (range from 21.8 to 62.7) at baseline. About 75% of the participants met the recommendations on minimal physical activity, both before the COVID-19 pandemic and during the lockdown. Weak statistical evidence for a decline in total physical activity in metabolic equivalent of task minutes per week (MET min/week) was found (estimate = -292, 95% CI from - ∞ to 74, -value = 0.09), with no evidence for a decrease in the three types of activity: walking (estimate = -189, 95% CI from - ∞ to 100, -value = 0.28), moderate-intensity activity (estimate = -200, 95% CI from - ∞ to 30, -value = 0.22) and vigorous-intensity activity (estimate = 80, 95% CI from - ∞ to 460, -value = 0.74). Across the three categories "high," "moderate," and "low" physical activity, 17% of the participants became less active during the lockdown while 29% became more active.

Conclusion: The COVID-19 pandemic did not result in a reduction in total physical activity levels among a sample of Swiss office workers during the first weeks of lockdown. Improved work-life balance and working times may have contributed to this finding.

Clinical Trial Registration: www.ClinicalTrials.gov, NCT04169646. Registered 15 November 2019 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04169646.
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http://dx.doi.org/10.3389/fpsyg.2021.620307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928288PMC
February 2021

The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis.

Int J Mol Sci 2021 Feb 13;22(4). Epub 2021 Feb 13.

Center of Experimental Rheumatology, Department of Rheumatology, University Hospital Zurich, University of Zurich, 8952 Schlieren, Switzerland.

Background: Pathological activation of cardiac fibroblasts is a key step in development and progression of cardiac fibrosis and heart failure. This process has been associated with enhanced autophagocytosis, but molecular mechanisms remain largely unknown.

Methods And Results: Immunohistochemical analysis of endomyocardial biopsies showed increased activation of autophagy in fibrotic hearts of patients with inflammatory cardiomyopathy. In vitro experiments using mouse and human cardiac fibroblasts confirmed that blockade of autophagy with Bafilomycin A1 inhibited fibroblast-to-myofibroblast transition induced by transforming growth factor (TGF)-β. Next, we observed that cardiac fibroblasts obtained from mice overexpressing transcription factor Fos-related antigen 2 (Fosl-2tg) expressed elevated protein levels of autophagy markers: the lipid modified form of microtubule-associated protein 1A/1B-light chain 3B (LC3BII), Beclin-1 and autophagy related 5 (Atg5). In complementary experiments, silencing of Fosl-2 with antisense GapmeR oligonucleotides suppressed production of type I collagen, myofibroblast marker alpha smooth muscle actin and autophagy marker Beclin-1 in cardiac fibroblasts. On the other hand, silencing of either LC3B or Beclin-1 reduced Fosl-2 levels in TGF-β-activated, but not in unstimulated cells. Using a cardiac hypertrophy model induced by continuous infusion of angiotensin II with osmotic minipumps, we confirmed that mice lacking either Fosl-2 (Ccl19CreFosl2flox/flox) or Atg5 (Ccl19CreAtg5flox/flox) in stromal cells were protected from cardiac fibrosis.

Conclusion: Our findings demonstrate that Fosl-2 regulates autophagocytosis and the TGF-β-Fosl-2-autophagy axis controls differentiation of cardiac fibroblasts. These data provide a new insight for the development of pharmaceutical targets in cardiac fibrosis.
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http://dx.doi.org/10.3390/ijms22041861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7917643PMC
February 2021
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