Karin Melsens

The role of endothelial cells in the vasculopathy of systemic sclerosis: A systematic review

INTRODUCTION Systemic sclerosis (SSc) is an autoimmune connective tissue disorder characterized by fibroproliferative vasculopathy, immunological abnormalities and progressive fibrosis of multiple organs including the skin. In this study, all English speaking articles concerning the role of endothelial cells (ECs) in SSc vasculopathy and representing biomarkers are systematically reviewed and categorized according to endothelial cell (EC) (dys)function in SSc. METHODS A sensitive search on behalf of the EULAR study group on microcirculation in Rheumatic Diseases was developed in Pubmed, The Cochrane Library and Web of Science to identify articles on SSc vasculopathy and the role of ECs using the following Mesh terms: (systemic sclerosis OR scleroderma) AND pathogenesis AND (endothelial cells OR marker). All selected papers were read and discussed by two independent reviewers. The selection process was based on title, abstract and full text level. Additionally, both reviewers further searched the reference lists of the articles selected for reading on full text level for supplementary papers. These additional articles went through the same selection process. RESULTS In total 193 resulting articles were selected and the identified biomarkers were categorized according to description of EC (dys)function in SSc. The most representing and reliable biomarkers described by the selected articles were adhesion molecules for EC activation, anti-endothelial cell antibodies for EC apoptosis, vascular endothelial growth factor (VEGF), its receptor VEGFR-2 and endostatin for disturbed angiogenesis, endothelial progenitors cells for defective vasculogenesis, endothelin-1 for disturbed vascular tone control, Von Willebrand factor for coagulopathy and interleukin (IL)-33 for EC-immune system communication. Emerging, relatively new discovered biomarkers described in the selected articles, are VEGF165b, IL-17A and the adipocytokines. Finally, myofibroblasts involved in tissue fibrosis in SSc can derive from ECs or epithelial cells through a process known as endothelial-to-mesenchymal transition. CONCLUSION This systematic review emphasizes the growing evidence that SSc is primarily a vascular disease where EC dysfunction is present and prominent in different aspects of cell survival (activation and apoptosis), angiogenesis and vasculogenesis and where disturbed interactions between ECs and various other cells contribute to SSc vasculopathy.

Nailfold Capillaroscopy and Clinical Applications in Systemic Sclerosis.

Capillary microscopy is a safe and non‐invasive tool to evaluate the morphology of the microcirculation typically affected in SSc. Next to being paramount for the “(very) early” diagnosis of SSc eyes are also geared toward capillaroscopy with the aim to be able to use it as a biomarker, especially in the prediction of future occurrence of DU. The following review will explain what capillary microscopy is and will focus additionally on studies evaluating the association between capillaroscopy and DU.

Stabilization of Microcirculation in Patients with Early Systemic Sclerosis with Diffuse Skin Involvement following Rituximab Treatment: An Open-label Study

To the Editor: Systemic sclerosis (SSc) is a multisystemic autoimmune disease characterized by fibrosis of the skin and internal organs, generalized microvasculopathy, and antibody response against various cellular antigens. Severe organ involvement occurs early in the course of diffuse cutaneous SSc (dcSSc) and has a bad prognosis1. Survival of the first years of the disease is associated with improved outcome. Therapies that may help the patient overcome this early period seem warranted2. Rituximab (RTX) has been reported as optional therapy in SSc3,4,5. Our group reported stabilization of internal organ involvement during a 2-year followup in an open pilot study of a 2–treatment course (months 0 and 6) of RTX in patients with early dcSSc6,7. In our pilot studies, modified Rodnan skin score (mRSS) decreased significantly after RTX course. The percent of decrease in the open pilot studies was corroborated by a similar decrease in the percentage of collagen score in blindly assessed histopathological skin analyses. Because SSc is characterized by a pronounced microangiopathy over time … Address correspondence to Dr. V. Smith, Department of Rheumatology, Ghent University Hospital, Faculty of Medicine and Health Sciences, Department of Internal Medicine, Ghent University, De Pintelaan 185, B – 9000 Ghent, Belgium. E-mail: vanessa.smith{at}ugent.be

Screening for pulmonary arterial hypertension in an unselected prospective systemic sclerosis cohort

Screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. The DETECT screening algorithm is recommended in a high-risk SSc subgroup. This study aims to compare prospectively the positive predictive value of screening using the DETECT algorithm and the 2009 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines, and to compare their cost-effectiveness in an unselected, day-to-day SSc population. Post hoc, screening according to the 2015 ESC/ERS guidelines using echocardiographic parameters alone (“2015 echo screening”) or combined with the DETECT algorithm (“2015 combined screening”) in high-risk subjects was analysed. 195 consecutive SSc patients included in the Ghent University Hospital SSc cohort were screened using different algorithms. The referral rate for right heart catheterisation was 32% (63 out of 195 patients) (46/4/13/34/40 patients using the DETECT algorithm/2009 guidelines/both/2015 echo screening/2015 combined screening). Right heart catheterisation was performed in 53 patients (84%) (36 (78%)/four (100%)/13 (100%)/28 (82%)/32 (80%) patients recommended by the DETECT algorithm/2009 guidelines/both/2015 echo screening/2015 combined screening). PAH was diagnosed in three patients (incidence 1.5%·year–1, 95% CI 0.5–4.4), in whom all algorithms recommended a right heart catheterisation. The positive predictive value was 6% (95% CI 2–17%; three out of 49 patients) for the DETECT algorithm, 18% (95% CI 6–41%; three out of 17 patients) for the 2009 guidelines, 23% (95% CI 8–50%; three out of 13 patients) for both, 11% (95% CI 4–27%; three out of 28 patients) for the 2015 echo screening and 9% (95% CI 3–24%; three out of 32 patients) for the 2015 combined screening. The cost was EUR224/80/90/112 per patient using the DETECT algorithm/2009 guidelines/2015 echo screening/2015 combined screening. Echocardiography may remain a candidate first step for PAH screening in SSc. Echocardiography remains a candidate first step in screening for PAH in an unselected systemic sclerosis population http://ow.ly/nuoh3096nRh

Two years follow-up of an open-label pilot study of treatment with rituximab in patients with early diffuse cutaneous systemic sclerosis

Abstract Objectives: Following results in open-label studies of rituximab in patients with systemic sclerosis, a Belgian three-centre initiative was launched to explore safety and efficacy of rituximab in early, diffuse cutaneous systemic sclerosis (dcSSc). Methods: Open-label study of 17 patients with early dcSSc, treated with two courses of rituximab, at month 0 and 6. Clinical examination, lung function testing, echocardiography, disease activity score (DAS) and functional status were performed at baseline and over 24 months of follow-up. Results: Modified Rodnan skin score (MRSS) changed significantly over time, with a mean of 25.5 (standard deviation [SD] 6.0) at baseline to 12.6 (SD 5.1) at month 24 (Mixed Model Analysis [MMA] p < 0.0001), which is a decrease of 51% at month 24 vs. baseline. DAS showed significant decrease over the total study period, with a score of 4.1 (SD 1.7) at baseline to 1.5 (SD 1.8) at month 24 (MMA p < 0.0001). Additionally, this was significant at all time points vs. baseline, both for MRSS and DAS. Internal organ status remained clinically stable throughout the study period. No statistically significant differences compared to baseline were found at the follow-up time points. Seven serious adverse events took place, all except for one, considered unrelated to study medication. Conclusions: This is the first multicentre Belgian collaboration investigating potential efficacy of rituximab in early dcSSc. Rituximab appears to be safe and tolerable and it may have beneficial effects on skin involvement, on overall disease activity and on stabilization of internal organ status in early dcSSc.

Automated assessment of absolute nailfold capillary number on videocapillaroscopic images: Proof of principle and validation in systemic sclerosis

Absolute nailfold capillary number should be a putative biomarker in selected rheumatic diseases but could be time‐consuming and not highly repeatable.

Prevalence and incidence of pulmonary arterial hypertension : 10-year follow-up of an unselected systemic sclerosis cohort

Introduction Early screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcome. Therefore, we evaluated the screening for PAH during the 10-year follow-up of an unselected prospective SSc cohort by calculating the prevalence and the incidence rate of PAH and we compared the screening before and after implementation of the 2009 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines. Methods Data were evaluated from each SSc-specific visit of 362 consecutive SSc patients included in the SSc Cohort of the Ghent University between May 2006 and December 2015. Results Of the 362 included patients, 23.2% had limited SSc, 59.9% limited cutaneous SSc and 16.9% diffuse cutaneous SSc. At baseline, one patient was already on PAH-specific treatment and eight patients were diagnosed with PAH, implicating a baseline PAH prevalence of 2.5% (9/362). During follow-up (median of 18 months [interquartile range: 0-54 months]), nine patients were diagnosed with incidental PAH, resulting in an incidence rate of 9.3/1000 person-years, 95% confidence intervals (95% CI): 4.3-17.7. Before the ESC/ERS guidelines, five PAH patients, all already diagnosed with prevalent PAH, were included in the cohort. After 2009, 13 patients (4 prevalent cases) were diagnosed with PAH, making the yearly incidence around 1% (0.82%-2.00%). Conclusions During 10-year follow-up in a cohort of 362 unselected SSc patients, the cumulative prevalence of PAH is 5% (18/362) and the incidence rate 9.3/1000 person-years, 95% CI: 4.3-17.7. Before implementation of the 2009 ESC/ERS screening algorithm, there were no incident cases.

THU0252 Nailfold capillaroscopy in systemic lupus erythematosus: a systematic review and critical appraisal

Background Systemic lupus erythematosus (SLE) is a rheumatic disease with common vascular involvement. Nailfold capillaroscopic changes have been described in SLE. Although, until today there is no clear role yet for capillaroscopy in classifying or staging the disease. Objectives To systematically review and critically appraise the literature on capillaroscopic changes described in SLE. Methods A sensitive search, on behalf of the EULAR study group on microcirculation in Rheumatic Diseases, was developed in Web Of Science, PubMed and Embase to identify all original research studies in which SLE patients had capillaroscopy. Two reviewers identified titles, abstracts and full texts. Exclusion criteria were: ACR criteria for SLE were not met, less than 5 patients were included in the study, there was no information on capillaroscopy in SLE, no original research or non-English language. All included articles underwent quality appraisal. Results were summarised according to density, dimensions, morphology, haemorrhages, semi quantitative assessment, qualitative assessment (see table) and correlation of capillaroscopic changes with clinical and laboratory parameters. Results From 172 articles captured, 36 articles were included in this review. The following capillaroscopic parameters were significantly more prevalent in SLE patients compared to healthy controls (see table): tortuous capillaries, abnormal morphology, haemorrhages, nailfold capillaroscopic score, “non-specific patterns” and “scleroderma like pattern”. Hairpin shaped capillaries were significantly more prevalent in healthy controls compared to SLE patients. For clinical and laboratory parameters, Raynauds phenomenon (RP), gangrene and 24 hours proteinuria were significantly correlated with capillaroscopic changes. Conclusions This first systematic review on capillaroscopy in SLE attests conclusive significant differences in morphology, haemorrhages, semi quantitative assessment, qualitative assessment and some clinical and laboratory parameters. Further large scale research is ongoing through the EULAR study group on microcirculation in Rheumatic Diseases to further define its role. Disclosure of Interest None declared

FRI0277 Six-Minute Walk Test in Systemic Sclerosis Patients without Interstitial Lung Disease and Pulmonary Arterial Hypertension: Table 1.

Background Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are the leading causes of death in Systemic Sclerosis (SSc). Although the six-minute walk test (6MWT) is used for evaluating ILD and PAH in clinical practice, no data are available on six-minute walk distance (6MWD) in SSc without ILD and PAH. Objectives This study wants to evaluate the 6MWT at baseline and 6-month follow-up in a cohort of unselected SSc patients without ILD and PAH. Methods Prospectively collected data of the 6MWTs at baseline and 6-month follow-up of 300 consecutive SSc patients, included in the Ghent University Hospital Systemic Sclerosis Cohort between May 2006 and April 2015 were analysed. Results 98% (286/292) of the SSc patients performed a 6MWT at baseline or 6-month visit, after exclusion of 8 of the 300 SSc patients due to logistic problems. Two patients were unable to perform a 6MWT due to leg amputation and 4 due to immobility. 76% of the patients were female with a mean age of 51±14 years. Six patients had PAH, five had ILD and four were not evaluated with HRCT. Eventually 271 SSc patients without ILD and PAH performed a 6MWT at baseline or 6-month visit and 193 at both moments. The mean 6MWD of those 271 SSc patients was 460±108m. Patients in the diffuse cutaneous (DcSSc) subgroup (422±118m) walked less than in the limited (LSSc) subgroup (476±109m, p=0.02) and tended to walk less than in the limited cutaneous (LcSSc) subgroup (463±101m, p=0.06). In 193 SSc patients without ILD and PAH who walked at both moments, there was no significant difference between the 6MWDs (mean difference 2.11m 95%CI [-6.75m; 10.98m], p=0.64).Table 1. 6MWD during the first 6MWT and the evolution of the 6MWD from baseline to 6-month visit in different subgroups of SSc patients without ILD and PAH N First 6MWD P N 6MWD T0 6MWD T6 r Mean Diff (95% CI) P mean ± SD mean ± SD mean ± SD SSc 271 460±108 *0.02 193 466±100 468±95 0.80 2 (−7; 11) 0.64 LSSc 70 476±109*#† #0.67 53 471±115 466±104 0.83 −5 (−23; 13) 0.58 LcSSc 156 463±101*#‡ †0.02 109 474±87 477±80 0.72 3 (−8; 15) 0.57 DcSSc 45 422±118*†‡ ‡0.06 31 432±111 441±121 0.87 10 (−12; 32) 0.38 N: number of patients, T0: baseline visit, T6: 6-month visit, 6MWD and mean difference expressed in meter, r: Pearsons correlation coefficient, Diff: difference. Conclusions In SSc, execution of the 6MWT is feasible, as 98% of the SSc patients were able to perform a test. The baseline mean 6MWD of 271 SSc patients without ILD and PAH is 460±108m and is clinically stable over a 6 months period. The DcSSc subgroup walks less than the LSSc subgroup and the LcSSc subgroup. Disclosure of Interest None declared