scholarly journals Genetic Susceptibility to Interstitial Lung Disease Associated with Systemic Sclerosis

2015 ◽  
Vol 9s1 ◽  
pp. CCRPM.S23312 ◽  
Author(s):  
Akiko Tochimoto ◽  
Yasushi Kawaguchi ◽  
Hisashi Yamanaka
Keyword(s):  
Systemic Sclerosis ◽  
Growth Factor ◽  
Interstitial Lung Disease ◽  
Connective Tissue ◽  
Human Leukocyte Antigen ◽  
Lung Disease ◽  
Genetic Susceptibility ◽  
Human Leukocyte ◽  
Tissue Growth ◽  
Leukocyte Antigen

Systemic sclerosis (SSc) is a connective tissue disease that is characterized by tissue fibrosis, microvasculopathy, and autoimmunity. Interstitial lung disease (ILD) is a common complication of SSc and is one of the frequent causes of mortality in SSc. Although the exact etiology of SSc remains unknown, clinical and experimental investigations have suggested that genetic and environmental factors are relevant to the pathogenesis of SSc and SSc-ILD. More than 30 genes have been identified as susceptibility loci for SSc, most of which are involved in immune regulation and inflammation. It is thought that the key pathogenesis of SSc-ILD is caused by the release of profibrotic mediators such as transforming growth factor β1 and connective tissue growth factor from lung cells induced by a persistent damage. This review presents the genetic susceptibility to SSc-ILD, including human leukocyte antigen and non-human leukocyte antigen genes, especially focusing on connective tissue growth factor.

scholarly journals AB0605 CLINICAL PROFILE AND CHEST HIGH-RESOLUTION COMPUTED TOMOGRAPHY (HRCT) FINDINGS IN PATIENTS WITH CONNECTIVE TISSUE DISEASES AND INTERSTITIAL LUNG DISEASE: EXPERIENCE OF A SINGLE REFERENCE RHEUMATOLOGY CENTER

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1598.2-1599
Author(s):  
I. Rusu ◽  
L. Muntean ◽  
M. M. Tamas ◽  
I. Felea ◽  
L. Damian ◽  
...  
Keyword(s):  
Computed Tomography ◽  
Systemic Sclerosis ◽  
High Resolution ◽  
Interstitial Lung Disease ◽  
Connective Tissue ◽  
Lung Disease ◽  
Interstitial Pneumonia ◽  
Connective Tissue Diseases ◽  
High Resolution Computed Tomography ◽  
Hrct Patterns

Background:Interstitial lung disease (ILD) is a common manifestation of connective tissue diseases (CTDs), and is associated with significant morbidity and mortality. Chest high-resolution computed tomography (HRCT) play an important role in the diagnosis of ILD and may provide prognostic information.Objectives:We aimed to characterize the clinical profile and chest HRCT abnormalities and patterns of patients diagnosed with CTDs and ILD.Methods:In this retrospective, observational study we included 80 consecutive patients with CTDs and ILD referred to a tertiary rheumatology center between 2015 and 2019. From hospital charts we collected clinical data, immunologic profile, chest HRCT findings. HRCT patterns were defined according to new international recommendations.Results:Out of 80 patients, 64 (80%) were women, with a mean age of 55 years old. The most common CTD associated with ILD was systemic sclerosis (38.8%), followed by polymyositis (22.5%) and rheumatoid arthritis (18.8%). The majority of patients had dyspnea on exertion (71.3%), bibasilar inspiratory crackles were present in 56.3% patients and 10% had clubbing fingers. Antinuclear antibodies (ANA) were present in 78.8% patients, and the most frequently detected autoantibodies against extractable nuclear antigen were anti-Scl 70 (28.8%), followed by anti-SSA (anti-Ro, 17.5%), anti-Ro52 (11.3%) and anti-Jo (7.5%). Intravenous cyclophosphamide therapy for 6-12 months was used in 35% of patients, while 5% of patients were treated with mycophenolate mofetil.The most frequent HRCT abnormalities were reticular abnormalities and ground glass opacity. Non-specific interstitial pneumonia (NSIP) was identified in 46.3% CTDs patients. A pattern suggestive of usual interstitial pneumonia (UIP) was present in 32.5% patients, mainly in patients with systemic sclerosis. In 21.3% patients the HRCT showed reticulo-nodular pattern, micronodules and other abnormalities, not diagnostic for UIP or NSIP pattern.Conclusion:Nonspecific interstitial pneumonia (NSIP) is the most common HRCT pattern associated with CTDs. Further prospective longitudinal studies are needed in order to determine the clinical and prognostic significance of various HRCT patterns encountered in CTD-associated ILD and for better patient management.References:[1]Ohno Y, Koyama H, Yoshikaua T, Seki S. State-of-the-Art Imaging of the Lung for Connective Tissue Disease (CTD). Curr Rheumatol Rep. 2015;17(12):69.[2]Walsh SLF, Devaraj A, Enghelmeyer JI, Kishi K, Silva RS, Patel N, et al. Role of imaging in progressive-fibrosing interstitial lung diseases. Eur Respir Rev. 2018;27(150)Disclosure of Interests:None declared

scholarly journals SAT0286 BIOLOGICAL CORRELATES OF RADIOGRAPHIC FEATURES OF INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS: AN IN DEPTH ANALYSIS OF BRONCHOALVEOLAR PROTEINS OF SCLERODERMA LUNG STUDY I PARTICIPANTS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1087.1-1088
Author(s):  
E. Volkmann ◽  
D. Tashkin ◽  
N. Li ◽  
G. Kim ◽  
J. Goldin ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Growth Factor ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Research Support ◽  
Radiographic Features ◽  
Depth Analysis ◽  
Specific Proteins ◽  
Clinical Measures ◽  
The Relationship

Background:Systemic sclerosis-related interstitial lung disease (SSc-ILD) involves a combination of inflammation, fibrosis and vascular pathology that is typically assessed on CT imaging as a mixture of ground-glass opacification (GGO) and fibrotic changes. We hypothesized that proteins recovered from bronchoalveolar lavage (BAL) could be used to probe the underlying pathobiology associated with GGO and fibrotic changes.Objectives:(1) To assess the relationship between 68 unique BAL proteins measured in participants of Scleroderma Lung Study (SLS) I1and radiographic and physiologic measures of ILD; (2) To identify inter-correlations among specific proteins to enlighten our understanding of how specific biological pathways contribute to SSc-ILD.Methods:Bronchoscopy was performed on 144 of the 158 participants in SLS I with 103 BAL samples available for analysis. BAL was lyophilized, concentrated 10X and used in a multiplex protein analysis for 68 different cytokines, chemokines and other factors. Kendall tau correlations were performed to assess the relationship between individual proteins and baseline measures of pulmonary function and quantitative CT scores for fibrosis, GGO and total ILD. Those proteins found to correlate significantly with at least 2 clinical measures of ILD were entered into a cluster analysis with inter-correlations expressed as a heatmap.Results:Significant correlations were observed between fibrosis scores and several biologic pathways including pro-fibrotic factors (transforming growth factor beta [TGF-β], platelet-derived growth factor [PDGF]), proteins involved in tissue remodeling (Matrix metallopeptidase [MMP]-1,7,8,9; Hepatocyte growth factor [HGF]), and those involved in monocyte/macrophage migration and activation (Monocyte chemoattractant protein [MCP]-1,3; macrophage colony-stimulating factor [MCSF]). These same pathways correlated with the diffusing capacity for carbon monoxide (DLCO). In contrast, GGO scores correlated primarily with immune and inflammatory mediators (interleukin [IL]-5,8,13,15, IL-1 receptor antagonist and interferon gamma) with only limited overlap to proteins that related to fibrosis. Vascular endothelial growth factor (VEGF) levels were lower in patients with more extensive GGO, fibrosis and diffusion impairment, suggesting that vascular changes are a central feature of SSc-ILD. Specific proteins were highly correlated with one another in a pattern suggesting biologically-related networks (Figure) that might provide additional insight regarding disease pathogenesis.Conclusion:Combining a diverse analysis of BAL proteins with the rich dataset available from SSc-ILD patients participating in SLS I, the study findings suggest the involvement of distinct biologic pathways, inter-related networks, and specific biologic signatures associated with unique radiographic features of ILD. The relationship of these factors to other SSc disease features, patient outcomes and as predictors of treatment responses will be studied in future analyses.References:[1]Tashkin DP, et al. NEJM 2006.Figure.Correlation heatmap of BAL proteins associated with at least 2 clinical measures of ILD in SSc patients. Absolute correlations are depicted, and darker colors signify stronger correlations.Disclosure of Interests:Elizabeth Volkmann Grant/research support from: Forbius, Corbus Pharmaceuticals, Consultant of: Boehringer Ingelheim, Forbius, Speakers bureau: Boehringer Ingelheim, Donald Tashkin: None declared, Ning Li: None declared, Grace Kim: None declared, Jonathan Goldin: None declared, Airi Harui: None declared, Michael Roth Grant/research support from: Genentech/Roche

scholarly journals OP0268 TREATMENT STATUS AFFECTS HOW PULMONARY BIOMARKERS PREDICT PROGRESSION OF SYSTEMIC SCLEROSIS-RELATED INTERSTITIAL LUNG DISEASE

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 163.1-163
Author(s):  
E. Volkmann ◽  
D. Tashkin ◽  
M. Leng ◽  
N. LI ◽  
G. Kim ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Growth Factor ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Transforming Growth Factor ◽  
Selection Process ◽  
Linear Regression Models ◽  
Research Support ◽  
Gm Csf ◽  
Treatment Status

Background:The course of interstitial lung disease (ILD) varies considerably in patients with systemic sclerosis (SSc), and no biomarkers have been found to consistently predict ILD progression in this population. Treatment may affect how a candidate biomarker correlates with improvement/worsening of SSc-ILD. We hypothesized that specific proteins recovered from bronchoalveolar lavage (BAL) would differentially predict progression of SSc-ILD based on whether a patient was receiving ILD therapy.Objectives:(1) To assess the relationship between 68 unique BAL proteins measured in participants of Scleroderma Lung Study (SLS) I1 and changes in radiographic extent of SSc-ILD; (2) To determine if treatment affects whether a specific protein predicts improvement or worsening of SSc-ILD.Methods:Bronchoscopy was performed on 144 of the 158 participants in SLS I (Cyclophosphamide [CYC] vs. placebo) with 103 BAL samples available for analysis. BAL was lyophilized, concentrated 10X and used in a multiplex protein analysis of 68 distinct cytokines, chemokines and growth factors. Quantitative imaging analysis (QIA) was used to calculate the extent of radiographic fibrosis (QLF) in the whole lung using HRCT of the chest at baseline and 12 months. Multivariable linear regression models were created to determine the key BAL proteins associated with change in QLF scores using a backward selection process adjusting for treatment arm and ILD severity. The bootstrap procedure was employed for internal validation.Results:A number of BAL proteins were significantly associated with change in QLF scores at 12 months; however, the directionality of these associations was often based on the presence/absence of treatment. For example, increased levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin (IL)-1, monocyte chemoattractant protein (MCP)-3, chemokine ligand (CCL)-5, transforming growth factor (TGF)-β, hepatocyte growth factor (HGF), stem cell factor (SCF), IL-4, TGF-α, were associated with worse QLF scores in patients who received placebo; whereas, increased levels of these same proteins were associated with improved QLF scores in patients who received CYC (Figure). Increased levels of Fractalkine were associated with worse in QLF scores, and increased levels of IL-7 were associated with improved QLF scores, regardless of treatment arm. In the multivariable model adjusting for treatment arm and baseline severity of ILD, IL-1, MCP-3, surfactant protein C, IL-7, and CCL-5 were independently associated with change in QLF scores.Figure 1.Example of a specific BAL protein (GM-CSF) that predicts worse QLF scores in patients receiving placebo (Group B, Red dotted line) and improved QLF scores in patients receiving CYC (Group A, Blue solid line). Shaded areas represent 95% confidence intervals.Conclusion:Proteins that mediate both inflammation and fibrosis differentially affected progression of SSc-ILD based on treatment status. Higher levels of certain proteins predicted worsening of ILD in patients receiving placebo, but improvement in patients receiving CYC. Measuring these proteins could help to identify patients who: (1) are at risk for ILD progression, and (2) may preferentially benefit from treatment with immunosuppression.References:[1]Tashkin DP, et al. NEJM 2006.Disclosure of Interests:Elizabeth Volkmann Consultant of: Boehringer Ingelheim, Grant/research support from: Corbus, Forbius, Donald Tashkin: None declared, Mei Leng: None declared, Ning Li: None declared, Grace Kim: None declared, Jonathan Goldin: None declared, Airi Harui: None declared, Michael Roth Grant/research support from: Genentech/Roche

scholarly journals The human leukocyte antigen and genetic susceptibility in human diseases

2019 ◽  
Vol 2 (3) ◽  
pp. 112-120
Author(s):  
Jinping Gao ◽  
Caihong Zhu ◽  
Zhengwei Zhu ◽  
Lili Tang ◽  
Lu Liu ◽  
...  
Keyword(s):  
Human Leukocyte Antigen ◽  
Genetic Susceptibility ◽  
Human Leukocyte ◽  
Human Diseases ◽  
Leukocyte Antigen

scholarly journals A study of respiratory system involvement in autoimmune connective tissue diseases: a marker of morbidity

2020 ◽  
Vol 6 (4) ◽  
pp. 532
Author(s):  
Neha T. Solanki ◽  
Sahana P. Raju ◽  
Deepmala Budhrani ◽  
Bharti K. Patel
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Connective Tissue ◽  
Pulmonary Function ◽  
Lung Disease ◽  
Pulmonary Function Tests ◽  
Tertiary Care ◽  
Connective Tissue Diseases ◽  
Cutaneous Manifestations ◽  
Respiratory Involvement

<p class="abstract"><strong>Background:</strong> The auto-immune connective tissue diseases (AICTD) are polygenic clinical disorders having heterogeneous overlapping clinical features. Certain features like autoimmunity, vascular abnormalities, arthritis/arthralgia and cutaneous manifestations are common to them. Lung involvement can present in AICTDs in form of: pleurisy, acute/ chronic pneumonitis, pulmonary artery hypertension (PAH), shrinking lung syndrome, diffuse alveolar damage, pulmonary embolism (PE), bronchiolitis obliterans organizing pneumonia, pulmonary infections, cardiogenic pulmonary edema, etc. High-resolution computed tomography (HRCT) plays an important role in identifying patients with respiratory involvement. Pulmonary function tests are a sensitive tool detecting interstitial lung disease.</p><p class="abstract"><strong>Methods:</strong> The present study is an observational study carried out on 170 patients of AICTD in department of Dermatology, Venereology and Leprosy at a tertiary care centre during a period of 2 years from October 2017 to August 2019. Detailed history, examination and relevant investigations like chest X-ray, pulmonary function test (PFT), HRCT thorax were done as indicated.<strong></strong></p><p class="abstract"><strong>Results:</strong> The overall incidence of respiratory involvement was 56.7% with maximum involvement in systemic sclerosis cases (82.8% of cases). 45.7% of patients of systemic lupus erythematosus had respiratory involvement, most common being pleural effusion in 11.5%. Impaired PFT’s were seen in 82.8% cases of systemic sclerosis (SSc)  and all cases of UCTD. Interstitial lung disease was seen in 34.7% and 25% cases of SSc and DM respectively. PAH was found in 15.2% cases of SSc and 9.8% cases of mixed connective tissue diseases.</p><p class="abstract"><strong>Conclusions:</strong> AICTD are multisystem disorders in which pulmonary involvement can be an important cause of morbidity to the patient and early detection is necessary for prevention of long-term respiratory complications.</p>

FRI0600 DIAGNOSTIC VALUE OF SERUM CONNECTIVE TISSUE GROWTH FACTOR IN RHEUMATOID ARTHRITIS

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 906-907
Author(s):  
R. Jiaqi ◽  
J. Zhao ◽  
L. Sun ◽  
Z. MA ◽  
X. Wang
Keyword(s):  
Rheumatoid Arthritis ◽  
Growth Factor ◽  
Interstitial Lung Disease ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Rheumatic Diseases ◽  
Diagnostic Value ◽  
Tissue Growth ◽  
Healthy Controls ◽  
Healthy Individuals

Background:Many autoantibodies are found in the serum of rheumatoid arthritis (RA) patients, including RF, ACPA and so on, which are essential for the disease diagnosis and prognosis judgment. However, 20-30% of patients are still seronegative, so more investigations are needed to find new biomarkers in RA.Objectives:To investigate the prevalence of serum connective tissue growth factor (CTGF) and the association with the clinical features in RA patients.Methods:Serum samples were obtained from 180 patients with RA, 168 patients with other rheumatic diseases, including 43 systemic lupus erythematosus (SLE), 34 osteoarthritis (OA), 17 primary Sjögren’s syndrome (pSS), 20 ankylosing spondylitis (AS), 23 psoriatic arthritis (PsA), 6 reactive arthritis (ReA), 20 systemic sclerosis (SSc), and 5 systemic vasculitis (SV), and 64 healthy individuals in Peking University Third Hospital. The clinical and laboratory data of patients with RA were collected. Levels of CTGF in serum were measured by ELISA. The cut-off value of CTGF was determined by 95 percent of the concentration of the healthy controls. Statistical analyses were performed using the SPSS 24.0 software. Associations between CTGF and the clinical features of RA were evaluated.Results:The prevalence of serum CTGF among RA patients (33.89%) was significantly higher than those of SLE (9.3%), OA (0%), AS (0%), pSS (0%), PsA (0%), ReA (0%), SSc(5%), SV(0%) and healthy controls (4.69%) (p<0.0001). The mean titer of serum CTGF in RA was also significantly higher than those in other rheumatic diseases and healthy controls (p<0.001). At the cutoff value of 264.30 pg/ml, the sensitivity, specificity, positive predictive value and negative predictive value of serum CTGF for RA were 33.89%, 96.55%, 88.41% and 55.45% respectively. Anti-cyclic citrullinated peptide (CCP) antibody (p<0.001), rheumatoid factor (p<0.001), IgG (p=0.025) and IgM (p=0.004) in CTGF-positive patients were higher than those in CTGF-negative patients. Besides, more patients with interstitial lung disease (ILD) were found in CTGF-positive RA.Conclusion:Serum CTGF, as a novel biomarker, has certain diagnostic value for RA. Further studies are necessary to get more knowledge for the diagnostic performance of CTGF in RA.References:[1] Ramazani Y, et al. (2018) Connective tissue growth factor (CTGF) from basics to clinics. Matrix Biol 68-69:44-66.[2] Nozawa K, F et al. (2009) Connective tissue growth factor promotes articular damage by increased osteoclastogenesis in patients with rheumatoid arthritis. Arthritis research & therapy 11 (6):R174.[3] Yang X, et al. (2017) Serum connective tissue growth factor is a highly discriminatory biomarker for the diagnosis of rheumatoid arthritis. Arthritis research & therapy 19 (1):257.[4] Wei JL, et al. (2018) Role of ADAMTS-12 in Protecting Against Inflammatory Arthritis in Mice By Interacting With and Inactivating Proinflammatory Connective Tissue Growth Factor. Arthritis & rheumatology (Hoboken, NJ) 70 (11):1745-1756.[5] Tang X, et al. (2018) Connective tissue growth factor contributes to joint homeostasis and osteoarthritis severity by controlling the matrix sequestration and activation of latent TGFbeta. Ann Rheum Dis 77 (9):1372-1380.Fig 1.Distribution of serum CTGF in RA, other rheumatic diseases and healthy control. Serum sample were from 180 patients with rheumatoid arthritis (RA), 168 patients with other rheumatic diseases and 64 healthy individuals (HC). Levels of serum CTGF were measured by CTGF ELISA kit. The cut-off value was 263.30 pg/mL (black horizontal dotted line); ***p <0.001Table 1. Demographic, clinical and laboratory features of total RA patients and grouped with serum CTGF.Abbreviations: RA=rheumatoid arthritis; SJC=swollen joint count; TJC=tender joint count; ESR=erythrocyte sedimentation rate; CRP=C-reactive protein; DAS=disease activity score; CCP=cyclic citrullinated peptid; RF=rheumatoid factor. CTGF=connective tissue growth factor; ILD= interstitial lung diseaseDisclosure of Interests:None declared

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