Systemic Sclerosis Disease Research Articles

Radiomics on slice-reduced versus full-chest computed tomography for diagnosis and staging of interstitial lung disease in systemic sclerosis: A comparative analysis

PurposeThe purpose of this study was to evaluate the efficacy of radiomics derived from slice-reduced CT (srCT) scans versus full-chest CT (fcCT) for diagnosing and staging of interstitial lung disease (ILD) in systemic sclerosis (SSc), considering the potential to reduce radiation exposure. Material and methodsThe fcCT corresponded to a standard high-resolution full-chest CT whereas the srCT consisted of nine axial slices. 1451 radiomic features in two dimensions from srCT and 1375 features in three dimensions from fcCT scans were extracted from 166 SSc patients. The study included first- and second-order features from original and wavelet-transformed images. We assessed the predictive performance of quantitative CT (qCT)-based logistic regression (LR) models relying on preselected features and machine learning workflows involving LR and extra-trees classifiers with data-driven feature selection. The area under the receiver operating characteristic curve (AUC) was used to estimate model performance. ResultsThe best models for diagnosis and staging ILD achieved AUC=0.85±0.08 and AUC=0.82±0.08 with srCT, and AUC=0.83±0.06 and AUC=0.76±0.08 with fcCT, respectively. srCT-based models showed slightly superior performance over fcCT-based models, particularly in 2D-radiomic analyses when interpolation resolution closely matched the original in-plane resolution. For diagnosis, the LR outperformed qCT-models, whereas for staging, the best results were obtained with a qCT-based model. ConclusionsRadiomics from srCT is an effective and preferable alternative to fcCT for diagnosing and staging SSc-ILD. This approach not only enhances predictive accuracy but also minimizes radiation exposure risks, offering a promising avenue for improved treatment decision support in SSc-ILD management.

Gastrointestinal disease in systemic sclerosis: the neglected organ system?

Identifying outcomes and clinical trial endpoints enabled the discovery of new inflammatory bowel disease (IBD) treatments. Herein, we describe efforts to advance the study of gastrointestinal (GI) manifestations in systemic sclerosis (SSc). Insights into the scope of the problem, as well as advancements in the measurement and treatment of SSc-GI, are underway. Proposed SSc esophageal endophenotypes are now defined, risk stratification methods are growing, and imaging and functional studies are now employed to guide therapeutic interventions. Additional progress is being made in characterizing the gut microbiome in patients with SSc. Research into the role of the immune response in the pathogenesis of SSc-GI disease is also ongoing, evolving simultaneously with the development of methods to facilitate data collection with real-time capture of diet, exercise, and medication data. Multidisciplinary teams are working to deepen our understanding of SSc-GI disease pathogenesis, to identify biomarkers for risk stratification and the assessment of disease activity, and to develop and validate outcomes and clinical trial endpoints to pave the way toward effective therapy for SSc-GI disease.

Treatment of interstitial lung disease in systemic sclerosis: guidelines and new clinical trial results.

Interstitial lung disease (ILD) is the leading cause of death in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). The American College of Rheumatology (ACR), in conjunction with the American College of Chest Physicians (CHEST), recently published clinical practice guidelines for the treatment of adults with systemic autoimmune rheumatic disease-associated ILD, including SSc-ILD. Herein, we summarize evidence from randomized trials evaluating the safety and efficacy of pharmacologic therapies for the treatment of SSc-ILD. In this review, we present findings from recent randomized controlled trials in SSc-ILD. The pharmacologic therapies discussed include immunosuppressive medications (mycophenolate, cyclophosphamide, rituximab, and tocilizumab) and antifibrotic medications (nintedanib and pirfenidone). Randomized trials provide an evidence base for the SSc-ILD treatment recommendations put forth in the ACR/CHEST Guidelines for the treatment of ILD in people with systemic autoimmune rheumatic diseases. These guidelines will help inform clinical practice and highlight areas in which further research is needed.

Assessment of interstitial lung disease in a systemic sclerosis patient cohort using photon-counting detector CT with ultra-high resolution and a 1024-pixel image matrix.

This study assessed the potential of ultra-high-resolution (UHR) and a 1024-matrix in photon-counting-detector CT (PCD-CT) for evaluating interstitial lung disease (ILD) in systemic sclerosis (SSc) patients. Sixty-six SSc patients who underwent ILD-CT screening on a first-generation PCD-CT were retrospectively included. Scans were performed in UHR mode at 100 kVp with two different matrix sizes (512x512 and 1024x1024) and reconstructed at slice thicknesses of 1.5 mm and 0.2 mm. Image noise, subjective image quality, and ILD changes (1) were evaluated on a 5-point Likert-scale by two independent readers. Interreader agreement for subjective image quality ranged from fair to almost perfect (Krippendorff-Alpha: 0.258-0.862). Overall image quality was highest for 1.5 mm/1024matrix images ((reader 1: 4 (4.4), reader 2: 5 (4.5)). Image sharpness was rated significantly better in 0.2 mm images (p < 0.001). Regarding ILD changes, 0.2 mm slice thickness outperformed 1.5 mm slice thickness significantly (p < 0.001), while there was no significant difference between the two matrix sizes. 1024 matrix size demonstrated superiority in evaluating coarse reticulations compared to 512matrix size. UHR mode with a 0.2 mm slice thickness showed enhanced image sharpness and improved visibility of ILD changes compared to standard reconstructions. This has the potential to enable the early detection of subtle disease manifestations. With the invention of PCD-CT different reconstruction algorithms need to be evaluated for specific pathologies. In our study ILD UHR mode with 0.2 mm slice thickness showed to be beneficial in the detection of parenchymal changes in patients with scleroderma.

Prevalence of metabolic syndrome patıents with systemic sclerosis

Objective: To determine the prevalence of metabolic syndrome (MetS) in Turkish systemic sclerosis (SSc) patients. Materials and Methods: In this cross-sectional, single-centre study, 76 SSc patients admitted to the outpatient clinic of our tertiary care hospital between July and September 2021 were included. The National Cholesterol Education Programme's Adult Treatment Panel (NCEP-ATP III) criteria were used to define metabolic syndrome (MetS). The relationship between MetS and SSc organ involvement and disease characteristics was investigated. Results: According to the ATP III criteria, 37 cases (48.7%) were identified as having MetS. The prevalance of MetS increased with advancing age (40-45 years: 25%, 46-60 years: 48.4%, &amp;gt;60 years: 62.9%). The cases were divided into two groups according to the presence or absence of MetS. Patients with MetS had higher mean age (58.2±9.4 vs. 51.6±13.5, p=0.015) and lower modified Rodnan skin scores (14 vs. 22, p=0.019). The groups were comparable regarding disease subtype, duration and activity, organs/systems involved and disease-related damage. Conclusion: Although the prevalence of MetS in SSc patients in our study was higher than that observed in the general population of our country, the prevalence of MetS did not increase when compared to the similar age group. MetS was thought to be related to age and gender predominance rather than the disease itself. Although mRSS was found to be significantly lower in patients with MetS, its sensitivity to predict MetS was found to be low. Nevertheless, our data suggest that the risk of MetS should be considered in SSc patients.

Racial and ethnic associations with interstitial lung disease and healthcare utilization in patients with systemic sclerosis.

Racial and ethnic differences in presentation and outcomes have been reported in systemic sclerosis (SSc) and SSc-interstitial lung disease (ILD). However, prior studies have limited diversity. We aim to evaluate if there are racial/ethnic differences associated with ILD, time intervals between SSc and ILD and with emergency department (ED) visit or hospitalization rates. Clinical and sociodemographic variables were extracted for 756 patients with SSc from longitudinal health records in an integrated health-system. Logistic regression models analyzed the association of covariates with ILD and age at SSc-ILD. Healthcare outcomes were analyzed with complementary log-log regression models. Overall, 33.7% of patients in the cohort had an ILD code, with increased odds for Asian (odds ratio [OR], 2.60; 95% confidence interval [CI], 1.29-5.28; p=0.008) compared with White patients. The predicted age in years of SSc-ILD was younger for Hispanic (estimate, -6.5; 95% CI, -13--0.21; p = 0.04) and Black/African American patients (-10; 95% CI -16--4.9; p < 0.001) compared with White patients. Black/African American patients were more likely to have an ILD code before an SSc code (59% compared with 20.6% of White patients), and the shortest interval from SSc to ILD (3 months). Black/African American (HR, 2.59; 95% CI 1.47-4.49; p = 0.001) and Hispanic patients (HR 2.29; 95% CI 1.37- 3.82; p = 0.002) had higher rates of an ED visit. We found that odds of SSc-ILD differed by racial/ethnic group, minoritized patients had earlier age of presentation, and greater rates of an ED visit.

Update on systemic sclerosis

The updates to the European recommendations and the German guidelines for the treatment of systemic sclerosis are expected shortly, which are very good evidence-based guidelines for all those treating the disease; however, there are still disease manifestations with insufficient studies and current study results that were published after the review of the literature for the guidelines and might be of interest to the reader. The aim of this work is to provide an overview of the publications in the last year that are interesting from the authors' point of view. The aim is to provide practically relevant information on the current state of knowledge that can supplement the guidelines. The pathogenesis of systemic sclerosis (SSc) is becoming better understood in its interplay between environmental factors and the development of autoantibodies. There have also been overviews of the manifestation and prognosis of cardiac involvement in the last year. The American Thoracic Society issued the first guidelines for the treatment of interstitial lung disease in SSc. There are an increasing number of studies that suggest that disease-modulating combination therapies, such as rituximab and mycophenolate mofetil (MMF) are beneficial. Work addressing the involvement of joints suggests that inflammatory changes are common. Current options for the treatment of gastrointestinal involvement are presented. The diagnosis and treatment of systemic sclerosis is making progress and many symptoms and complications are treatable. Nevertheless, much remains to be done to improve the quality of life of the patients.

Spectrum of renal disease in scleroderma other than scleroderma renal crisis: A review of the literature.

Systemic sclerosis (SSc) is a multi-system rheumatic disease characterized by vascular and fibrotic manifestations that can affect practically every organ. Scleroderma renal crisis (SRC) is the most common renal manifestation of SSc. However, with the use of angiotensin-converting enzyme inhibitors (ACEi), the morbidity and mortality associated with SRC has significantly reduced. Renal manifestations in SSc other than SRC have been generally under-recognized and can be left untreated, which can lead to grave consequences in this patient population. In this article, we will describe the spectrum of renal disease in SSc besides SRC. A literature search was conducted on PubMed and Cochrane from inception to December 2022 using medical subject headings (MeSH) terms for "scleroderma", "systemic sclerosis" combined with "renal injury", and "renal dysfunction". We included case reports, case series, observational studies, and literature reviews. The initial search revealed 393 articles. After the exclusion of duplicates and non-relevant articles, data was included from 30 articles and 45 patients. The mean age was 55.2 years, 9 males (20%) and 36 females (80%). The most reported renal manifestations included: ANCA-associated vasculitis (n=22), penicillamine-induced renal injury (n=8), oxalate nephropathy (n=5), Goodpasture syndrome (n=4), nephrotic range proteinuria (n=2), renal artery stenosis (n=2), membranous glomerulonephritis (n=1), and Evans syndrome (n=1). The spectrum of kidney involvement in SSc can range from asymptomatic reduction of the glomerular filtration rate to life-threatening scleroderma renal crisis. Therefore, it is essential that physicians closely monitor renal function in these patients for any emerging renal dysfunction.

Towards a comprehensive approach to the management and prognosis of systemic sclerosis's patients: The role of comorbidities in the SPRING-SIR registry

ObjectivesThe current knowledge about the role of comorbidities in systemic sclerosis (SSc) is limited. Therefore, the aim of this study was to evaluate the prevalence of comorbidities and their impact on disease activity and prognosis in the Systemic sclerosis PRogression INvestiGation (SPRING) registry. MethodsSSc patients from the SPRING registry, fulfilling the ACR/EULAR 2013 classification criteria, with complete data on baseline comorbidities were enrolled. The Charlson comorbidity index (CCI) was used to quantify the overall comorbidity burden. The disease activity was calculated using the revised EUSTAR activity index (AI). The impact of SSc features on CCI, the effect of CCI on SSc disease activity and mortality were tested with multivariable regression models. ResultsAmong 1910 SSc patients enrolled, 67.3 % had at least one comorbidity at baseline. The most frequent comorbidities were systemic arterial hypertension (23.7 %), osteoporosis (12.9 %) and dyslipidemia (11 %). The mean value of CCI score was 2.0 ± 1.8. When patients were grouped according to increasing levels of CCI, a clear separation in the distribution of SSc-related clinical features could be observed. Among over 900 patients with available follow-up, no association between baseline CCI and changes in disease activity was observed. Conversely, the risk of death over time was independently predicted by both CCI and AI. ConclusionsComorbidities and disease activity independently impact on the prognosis of SSc patients. This suggests that the management of comorbidities, together with the reduction of disease activity, is fundamental to improve patient survival.

Concordance and Prognostic Relevance of Different Definitions of Systemic Sclerosis Interstitial Lung Disease Progression.

Interstitial lung disease (ILD) in systemic sclerosis (SSc) is a common complication that has varied progression rate and prognosis. Different progression definitions are available: include minimal clinically important worsening of forced vital capacity (FVC MCIW), EUSTAR (EUropean Scleroderma Trials and Research group) progression, OMERACT (Outcome Measures in Rheumatology Clinical Trials) progression, and Erice ILD working group progression. Pulmonary function and symptoms changes may act as specific confounding factors applying these definitions in SSc. To assess the concordance and prognostic value of four different definitions in SSc-ILD patients overall and specific clinical groups. Progression status in consecutive SSc-ILD patients was assessed over 24 months, 60-month disease-related mortality risk was compared between progressors and non-progressors using the four definitions. Among 245 patients, 26 SSc-related deaths were reported. Mortality was linked to progression for FVC MCIW (HR 2.27, 95% CI 1.03-4.97), OMERACT (HR 2.90, 95% CI 1.28-6.57), and Erice definitions (HR 11.02, 95% CI 2.38-51.08). The association between progression and mortality was poor in patients with disease duration ≥3 years, mild functional impairment, and pulmonary artery systolic pressure (PASP)≥40 mmHg. Erice criteria appeared superior in patients with duration ≥3 years, limited cutaneous variant, and PASP<40 mmHg. OMERACT criteria performed better in diffuse cutaneous variant patients with severe functional impairment. The four evaluated definitions of progression in SSc-ILD are not interchangeable, resulting in up to a third of cases being classified differently based on the adopted criteria, and presenting different prognostic values, particularly within specific clinical groups.

Preventive effects of early immunosuppressive treatment on the development of interstitial lung disease in systemic sclerosis.

Hypothesizing that early treatment yields improved prognosis, we aimed to investigate how the timing of immunosuppressive treatment relates to interstitial lung disease (ILD) development and the course of pulmonary function in systemic sclerosis (SSc). A cohort was created using data from the EUSTAR database and Nijmegen Systemic Sclerosis cohort, including adult patients who started their first immunosuppressive treatment (ie mycophenolate mofetil, methotrexate, cyclophosphamide, tocilizumab or rituximab) after SSc diagnosis, and no signs of ILD on high-resolution CT. ILD-free survival and the course of forced vital capacity % predicted (ppFVC) were assessed for up to 5 years follow-up comparing patients who started early (disease duration ≤ 3 years) vs late with immunosuppression. 1052 patients met the eligibility criteria. The early treatment group (n = 547, 52%) showed a higher prevalence of male sex, diffuse cutaneous subtype (53.1% vs 36.5%), and anti-topoisomerase-I antibody (ATA, 51.1% vs 42.7%). Most patients were treated with methotrexate (60.1%), whereas only a few patients were treated with biologicals (1.7%). The incidence of ILD was 46.6% after mean (SD) 3.6(1.4) years; the hazards ratio for ILD in the early treatment group was 1.13 (95% CI: 0.93-1.38) after adjustment for confounders. PpFVC trajectories were comparable between groups. Our findings did not confirm a preventive role of early initiation of immunosuppressive therapy vs late initiation on ILD development. However, our findings should be interpreted with caution, considering the high inflammatory, ATA-positive enriched nature of the cohort, confounding by indication, and very few patients were treated with biologicals.

Effect of ambrisentan in patients with systemic sclerosis and mild pulmonary arterial hypertension: long-term follow-up data from EDITA study

BackgroundIn the EDITA trial, patients with systemic sclerosis (SSc) and mild pulmonary vascular disease (PVD) treated with ambrisentan had a significant decline of pulmonary vascular resistance (PVR) but not of mean pulmonary arterial pressure (mPAP) vs. placebo after six months. The EDITA-ON study aimed to assess long-term effects of open label therapy with ambrisentan vs. no pulmonary arterial hypertension (PAH) therapy.MethodsPatients who participated in the EDITA study and received regular follow-up were included in EDITA-ON. Clinical, echocardiographic, laboratory, exercise and hemodynamic parameters during follow-up were analysed. The primary endpoint was to assess whether continued treatment with ambrisentan vs. no treatment prevented the development of PAH according to the new definition.ResultsOf 38 SSc patients included in the EDITA study four were lost to follow-up. Of the 34 remaining patients (age 55 ± 11 years, 82.1% female subjects), 19 received ambrisentan after termination of the blinded phase, 15 received no PAH medication. The mean follow-up time was 2.59 ± 1.47 years, during which 29 patients underwent right heart catheterization. There was a significant improvement of mPAP in catheterised patients receiving ambrisentan vs. no PAH treatment (-1.53 ± 2.53 vs. 1.91 ± 2.98 mmHg, p = 0.003). In patients without PAH treatment 6/12 patients had PAH vs. 1/17 of patients receiving ambrisentan (p < 0.0001).ConclusionIn SSc patients with early PVD, the development of PAH and/or deterioration was less frequent among patients receiving ambrisentan, indicating that early treatment and close follow-up could be beneficial in this high-risk group. Future trials in this field are needed to confirm these results.

Racial variability in immune responses only partially explains differential systemic sclerosis disease severity

ObjectiveTo understand if autoantibodies account for racial variation in disease severity, we compared autoantibody distribution and associated phenotype between self-identified black and white systemic sclerosis (SSc) patients.Methods803 black and 2178...

Systematic literature review to inform the Portuguese recommendations for the management of Raynaud's phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases.

To perform a systematic literature review (SLR) aimed at evaluating the efficacy and safety of pharmacological and non-pharmacological treatments for Raynaud's phenomenon (RP) and digital ulcers (DU) in patients with systemic sclerosis (SSc) and other connective tissue diseases (CTD), in order to inform the Portuguese recommendations for managing RP and DU in these patients. A SLR was conducted until May 2022 to identify studies assessing the efficacy and safety of pharmacological and non-pharmacological interventions for RP and DU in SSc and other CTD. Eligible study designs included randomized controlled trials (RCTs), controlled clinical trials, and their extensions for assessing efficacy and safety of interventions. Observational studies with a comparator were included for evaluating the efficacy and safety of non-pharmacological interventions and safety of pharmacological interventions. The risk of bias of each study was assessed using standard tools. Out of 71 publications meeting the inclusion criteria, 59 evaluated pharmacological and 12 non-pharmacological interventions. We found moderate quality evidence supporting the efficacy of calcium channel blockers, phosphodiesterase-5 inhibitors, and intravenous prostacyclin analogues in reducing RP frequency, severity, and duration. Intravenous iloprost had a small to moderate effect size in improving DU healing. Phosphodiesterase-5 inhibitors were effective in reducing total DU count, new DU occurrence, and enhancing DU healing. Bosentan effectively prevented new DU in SSc patients. No new safety concerns were associated with these treatments. The studies on non-pharmacological interventions were, in general, of low quality, and had a small sample size. Warming measures decreased frequency and duration of RP attacks; laser therapy improved RP-related outcomes; local oxygen-ozone therapy improved RP outcomes as an add-on therapy; bone marrow mononuclear cell implantation improved DU-associated pain; periarterial sympathectomy and vascular bypass reduced DU number and finger amputation risk. The available evidence supports the efficacy and safety of pharmacological interventions, namely nifedipine, sildenafil, iloprost, and bosentan in treating RP and DU in patients with SSc and other CTD. Scarce and low-quality evidence does support the use of some non-pharmacological interventions but with only a modest effect size. This SLR underscores the limited availability of high-quality evidence for determining the optimal treatment.

Portuguese Recommendations for the management of Raynaud’s phenomenon and digital ulcers in systemic sclerosis and other connective tissue diseases

Objective: To develop evidence-based recommendations for the non-pharmacological and pharmacological management of Raynaud’s phenomenon (RP) and digital ulcers (DUs) in patients with systemic sclerosis and other immune- mediated connective tissue diseases (CTDs). Methods: A task force comprising 21 rheumatologists, 2 surgeons (vascular and plastic), 2 nurses, and 1 patient representative was established. Following a systematic literature review performed to inform the recommendations, statements were formulated and discussed during two meetings (one online and one in-person). Levels of evidence, grades of recommendation (GoR), and level of agreement (LoA) were determined. Results: Five overarching principles and 13 recommendations were developed. GoR ranged from A to D. The mean ± standard difference (SD) LoA with the overarching principles and recommendations ranged from 7.8±2.1 to 9.8±0.4. Briefly, the management of RP and DUs in patients with CTDs should be coordinated by a multidisciplinary team and based on shared decisions with patients. Nifedipine should be used as first-line therapy for RP and/ or DUs. Sildenafil, tadalafil, and/or iloprost IV are second-line options for severe and/or refractory patients with RP and/or DUs. Sildenafil, tadalafil and/or Iloprost IV, should be prescribed for healing and prevention (also including bosentan) of DUs. In patients with RP and/or DUs, non-pharmacological interventions might be considered as add-ons, but there is limited quality and quantity of scientific evidence supporting their use. Conclusions: These recommendations will inform rheumatologists, specialist nurses, other healthcare professionals, and patients about a comprehensive and personalized management of RP and DUs. A research agenda was developed to address unmet needs, particularly for non-pharmacologic interventions.

The impact of gastroesophageal reflux disease and its treatment on interstitial lung disease outcomes

BackgroundTo determine the relationship between gastroesophageal reflux disease (GORD) and its treatment and interstitial lung disease in patients with systemic sclerosis (SSc).MethodsSSc patients from the Australian Scleroderma Cohort Study (ASCS) were included. GORD was defined as self-reported GORD symptoms, therapy with a proton pump inhibitor (PPI) or histamine 2 receptor antagonist (H2RA) and/or the presence of reflux oesophagitis diagnosed endoscopically. The impact of GORD and its treatment on ILD features (including severity and time to ILD development) and survival was evaluated.ResultsGORD was a common manifestation affecting 1539/1632 (94%) of SSc patients. GORD affected 450/469 (96%) of those with SSc-ILD cohort. In SSc-ILD, there was no relationship between the presence of GORD or its treatment and time to ILD development or ILD severity. However, GORD treatment was associated with improved survival in those with ILD (p = 0.002). Combination therapy with both a PPI and a H2RA was associated with a greater survival benefit than single agent therapy with PPI alone (HR 0.3 vs 0.5 p < 0.050 respectively).ConclusionGORD is a common SSc disease manifestation. While the presence or treatment of GORD does not influence the development or severity of ILD, aggressive GORD treatment, in particular with a combination of PPI and H2RA, is associated with improved survival in those with SSc-ILD.

Virus-Induced MicroRNA Modulation and Systemic Sclerosis Disease.

MicroRNAs (miRNAs) are short noncoding RNA sequences that regulate gene expression at the post-transcriptional level. They are involved in the regulation of multiple pathways, related to both physiological and pathological conditions, including autoimmune diseases, such as Systemic Sclerosis (SSc). Specifically, SSc is recognized as a complex and multifactorial disease, characterized by vascular abnormalities, immune dysfunction, and progressive fibrosis, affecting skin and internal organs. Among predisposing environmental triggers, evidence supports the roles of oxidative stress, chemical agents, and viral infections, mostly related to those sustained by beta-herpesviruses such as HCMV and HHV-6. Dysregulated levels of miRNA expression have been found in SSc patients compared to healthy controls, at both the intra- and extracellular levels, providing a sort of miRNA signature of the SSc disease. Notably, HCMV/HHV-6 viral infections were shown to modulate the miRNA profile, often superposing that observed in SSc, potentially promoting pathological pathways associated with SSc development. This review summarizes the main data regarding miRNA alterations in SSc disease, highlighting their potential as prognostic or diagnostic markers for SSc disease, and the impact of the putative SSc etiological agents on miRNA modulation.

The Role of TLR7 and TLR9 in the Pathogenesis of Systemic Sclerosis.

The bleomycin-induced scleroderma model is a well-established and dependable method for creating a mouse model of SSc (systemic sclerosis). In the field of skin connective tissue diseases, increasing evidence from clinical and animal experiments suggests that TLRs (Toll-like receptors) play an important role in several diseases. This study aimed to determine the role of TLR7 (Toll-like receptor 7) and TLR9 (Toll-like receptor 9) in the mechanisms of immune abnormalities and fibrosis in SSc. This study used TLR7-KO mice (TLR7-knockout mice with a balb/c background) and TLR9-KO mice (TLR9-knockout mice with a balb/c background) as well as WT mice (wild-type balb/c mice). All three kinds of mice were induced by BLM (bleomycin) in a scleroderma model as the experimental group; meanwhile, WT mice treated with PBS (phosphate-buffered saline) were used as the control group. We analyzed the fibrotic phenotype and the immunological abnormality phenotype of TLR7-deficient and TLR9-deficient mice in the SSc disease model using flow cytometry, RT-PCR (reverse transcription-polymerase chain reaction), a histological examination, and IHC (immunohistochemical staining). In a mouse model of SSc disease, the deletion of TLR7 attenuated skin and lung fibrosis, while the deletion of TLR9 exacerbated skin and lung fibrosis. The deletion of TLR7 resulted in a relative decrease in the infiltration and expression of various pro-inflammatory and fibrotic cells and cytokines in the skin. On the other hand, the deletion of TLR9 resulted in a relative increase in the infiltration and expression of various pro-inflammatory and cytokine-inhibiting cells and cytokines in the skin. Under the influence of pDCs (plasmacytoid dendritic cells), the balances of Beff/Breg (IL-6 + CD19 + B cell/IL-10 + CD19 + B cell), Th17/Treg (IL-17A + CD4 + T cell/Foxp3 + CD25 + CD4 + T cell), M1/M2 (CD86 + macrophage/CD206 + macrophage), and Th1/Th2 (TNFα + CD3 + CD4 + T cell/IL-4 + CD3 + CD4 + T cell) were biased towards the suppression of inflammation and fibrosis as a result of the TLR7 deletion. Comparatively, the balance was biased towards promoting inflammation and fibrosis due to the TLR9 deletion. In the SSc model, TLR7 promoted inflammation and fibrosis progression, while TLR9 played a protective role. These results suggest that TLR7 and TLR9 play opposite roles in triggering SSc to produce immune system abnormalities and skin fibrosis.

Risk Factors and Biomarkers for Interstitial Lung Disease and Pulmonary Arterial Hypertension in Systemic Sclerosis: Experience of Two Tertiary Centers in Turkey

Purpose: To define the clinical and laboratory characteristics of patients with systemic sclerosis (SSc), and to investigate the risk factors affecting the prevalence of interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH), which are important causes of morbidity and mortality. Patients and methods: 88 patients with SSc were compared according to the presence of ILD and PAH. ILD was confirmed by chest computed tomography, and PAH was suspected and considered probable PAH when right ventricular systolic pressure was &gt;40 mmHg according to echocardiography. Results: Of the 88 patients, 44.3% had diffuse-type and 55.7% had limited-type SSc. Diffuse type, percentages of positive anti-scleroderma-70 (anti-Scl70) antibody and anti-centromere antibody, white blood cell (WBC), platelet, erythrocyte sedimentation rate (ESR), smoking, and presence of the sclerodactyly and telangiectasia differed significantly in SSc with ILD group. The positive titer of anti-Scl70 antibody (odds ratio (OR)=6.124, p=0.004), platelet count (OR=0.138, p=0.002), ESR (OR=1.042, p=0.035) and presence of telangiectasia (OR=10.571, p=0.001) were associated with ILD in patients with SSc. Also, while diffuse-type (OR=0.223, p=0.010), the presence of sclerodactyly (OR=11.112, p=0.028) and telangiectasia (OR=3.861, p=0.020) were risk factors for the development of ILD in nonspecific interstitial pneumonia pattern, anti-Scl-70 antibody positivity (OR=12.921, p=0.019) and high ESR (OR=1.034, p=0.030) were found to be risk factors for the development of usual interstitial pneumonia pattern. Conclusion: Positive titer of the anti-Scl70 antibody, diffuse type, presence of telangiectasia, and high ESR were independently associated with ILD in SSc patients.

#2936 Chronic kidney disease in systemic sclerosis

Abstract Background and Aims Systemic sclerosis is a heterogeneous autoimmune disease with multiorgan involvement. To assess the clinical and epidemiological manifestations of patients with SSc who present CKD, and its implication in the prognosis and its importance in early detection. Method Selected 102 Caucasian patients (12 men and 90 women) diagnosed with SSc who were seen consecutively in the Scleroderma Unit at Vall d'Hebron Hospital since 1980. The following demographic variables were collected: sex, age, common cardiovascular risk factors (diabetes mellitus, hypertension, dyslipidemia), age at clinical onset, age at diagnosis, skin subtype of SSc according to the LeRoy and Medsger classification, visceral conditions, osteoarticular conditions, capillaroscopic pattern, biochemical parameters of renal function and immunological alterations, renal morphological alterations by ultrasound, and treatments. Results Overall, 102 SSc patients were included, of whom 24 (23.5%) had renal failure. The mean plasma creatinine value was 0.92 mg/dl and the mean GFR by CKD-EPI was 74.80 ml/min. The 76.5% had GFRe ≥60 ml/min (SScCKD-), with mean serum creatinine 0.85 ± 0.17 mg/dl and mean GFRe 82.13 ml/min (SD 20.53 ml/min); 23.5% had GFRe &amp;lt;60 ml/min (SScCKD+), in them mean serum creatinine was 1.09 ± 0.15 mg/dl and mean GFRe was 51.29 ml/min (SD 6.68 ml/min). By stage: 18 patients had G1 stage, 60 patients had G2 stage, 18 patients had GFR 3a and 6 patients GFR G3b. No proteinuria or hematuria was detected in any of the patients. In univariate analysis, limited cutaneous subtype was significantly more frequent in the SScCKD+ group (20, 83.3% vs. 44, 56.4%, p = 0.017) and the diffuse cutaneous subtype was more frequent in the SScCKD- group (0, 0% vs. 23, 29.4%, p &amp;lt; 0.001). In the study of associated antibodies, ACAs (20, 83.3% vs. 36, 46.1%, p = 0.001) were statistically significantly more frequent in the SScCKD+ group. No ATA were detected in SScCKD+ patients while in the SScCKD- group 25.6% had ATA (p = 0.003). Pulmonary involvement in the form of PAH was significantly more frequent in the SScCKD+ group (13, 54.1% vs. 19, 24.3%, p&amp;lt; 0.05). In pulmonary involvement in the form of ILD no differences were found (9, 37.5% vs. 37, 47.4% in SScCKD+ and SScCKD- patients, respectively). Regarding PFR results, there were no differences in the percentage of patients with FVC below 70% or 50% of the expected value (6, 25% vs. 15, 19.2% and 1, 4.1% vs. 4, 5.1%, respectively). Significant differences were found in mortality in the two groups (12, 50% vs. 16, 20.5%, in the SScCKD+ and SScCKD- group, respectively, p &amp;lt; 0.05), but not in the causes of death. Conclusion The presence of CKD in SSc conferred a clinical profile and prognosis.