Antifibroblast antibodies from systemic sclerosis patients bind to α-enolase and are associated with interstitial lung disease

Objective:To identify target antigens of antifibroblast antibodies (AFA) in systemic sclerosis (SSc) patients.Patients and Methods:In the first part, sera from 24 SSc patients (12 with pulmonary arterial hypertension (PAH) and 12 without) and 36 idiopathic PAH patients, tested in pooled sera for groups of three, were compared with a sera pool from 14 healthy controls (HC). Serum IgG reactivity was analysed by the use of a two-dimensional electrophoresis and immunoblotting technique with normal human fibroblasts antigens. In the second part, serum IgG reactivity for two groups: 158 SSc, 67 idiopathic PAH and 100 HC; and 35 SSc and 50 HC was tested against α-enolase from Saccharomyces cerevisiae and recombinant human (rHu) α-enolase, respectively, on ELISA.Results:In the first part, α-enolase was identified as a main target antigen of AFA from SSc patients. In the second part, 37/158 (23%) SSc patients, 6/67 (9%) idiopathic PAH patients and 4/100 (4%) HC (p<0.001) had anti-S cerevisiae α-enolase antibodies; 12/35 (34%) SSc patients and 3/50 (6%) HC had anti-rHu α-enolase antibodies (p = 0.001). In SSc, the presence of anti-S cerevisiae α-enolase antibodies was associated with interstitial lung disease (ILD), decreased total lung capacity (73.2% vs 89.7%; p<0.001) and diffusion capacity for carbon monoxide (47.4% vs 62.3%; p<0.001), and antitopoisomerase 1 antibodies (46% vs 21%; p = 0.005) but not anticentromere antibodies (11% vs 34%; p = 0.006). Results were similar with rHu α-enolase testing.Conclusion:In SSc, AFA recognise α-enolase and are associated with ILD and antitopoisomerase antibodies.

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Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease

Journal of Scleroderma and Related Disorders ◽

10.1177/2397198318764780 ◽

2018 ◽

Vol 3 (3) ◽

pp. 242-248 ◽

Cited By ~ 6

Author(s):

Matthew Moll ◽

Romy B Christmann ◽

Yuqing Zhang ◽

Michael L Whitfield ◽

Yu Mei Wang ◽

...

Keyword(s):

Gene Expression ◽

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Interstitial Lung Disease ◽

Arterial Hypertension ◽

Lung Disease ◽

Expression Profiles ◽

Area Under The Curve ◽

Gene Expression Profiles ◽

Pulmonary Arterial

Objective: Pulmonary arterial hypertension and interstitial lung disease are major causes of mortality in systemic sclerosis. We used a previously identified microarray biomarker to determine whether systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease patients demonstrate distinct gene expression profiles. Methods: Peripheral blood mononuclear cells were collected from healthy controls ( n = 10), systemic sclerosis patients without pulmonary hypertension (systemic sclerosis-no pulmonary arterial hypertension, n = 39), and systemic sclerosis-pulmonary arterial hypertension patients ( n = 21; mean pulmonary arterial pressure ≥25, pulmonary capillary wedge pressure ≤15, and pulmonary vascular resistance ≥3 Wood units) diagnosed by right heart catheterization. Systemic sclerosis-interstitial lung disease patients were defined as those with evidence of fibrosis on chest computed tomography and significant restriction (forced vital capacity <70% predicted, n = 11). Systemic sclerosis-pulmonary arterial hypertension biomarker included 69 genes selected by unbiased statistical screening of three publicly available microarray studies. RNA levels were measured by NanoString Technologies. Gene expression levels that were significantly correlated with pulmonary arterial hypertension (multiple statistical measures) were chosen as inputs into a forward selection logistic regression model. Results: When interstitial lung disease patients were included ( n = 64), four genes (S100P, CD8B1, CCL2, and TIMP1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.83). Without interstitial lung disease patients ( n = 53), two genes (THBS1 and CD8B1) and male sex predicted pulmonary arterial hypertension with a high level of accuracy (area under the curve = 0.80). When examining systemic sclerosis patients with borderline elevated pulmonary pressures (mean pulmonary arterial pressure = 21–24 mmHg), gene expression changes closely resembled the systemic sclerosis-pulmonary arterial hypertension group, except for THBS1. Conclusion: Systemic sclerosis-pulmonary arterial hypertension and systemic sclerosis-interstitial lung disease have similar but distinct gene expression profiles. Many gene expression changes occur early in the disease course, potentially allowing early detection. THBS1 appears to be an important mediator in the development of pulmonary arterial hypertension-predominant phenotype. Further prospective investigation is warranted.

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Faculty Opinions recommendation of Patients with systemic sclerosis-associated pulmonary arterial hypertension express a genomic signature distinct from patients with interstitial lung disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.733493332.793568478 ◽

2019 ◽

Author(s):

Todd Bull

Keyword(s):

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Interstitial Lung Disease ◽

Arterial Hypertension ◽

Lung Disease ◽

Genomic Signature ◽

Pulmonary Arterial

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Systemic sclerosis-related pulmonary hypertension associated with interstitial lung disease: Impact of pulmonary arterial hypertension therapies

Arthritis & Rheumatism ◽

10.1002/art.30423 ◽

2011 ◽

Vol 63 (8) ◽

pp. 2456-2464 ◽

Cited By ~ 75

Author(s):

Jérôme Le Pavec ◽

Reda E. Girgis ◽

Noah Lechtzin ◽

Stephen C. Mathai ◽

David Launay ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Interstitial Lung Disease ◽

Arterial Hypertension ◽

Lung Disease ◽

Disease Impact ◽

Pulmonary Arterial

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FRI0399 Improved survival in patients with systemic sclerosis (SSC)-related pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) treated with aggressive use of pah therapy.

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2013-eular.1526 ◽

2013 ◽

Vol 72 (Suppl 3) ◽

pp. A508.2-A509

Author(s):

E. Volkmann ◽

R. Saggar ◽

N. Borazan ◽

B. Torres ◽

H. Agrawal ◽

...

Keyword(s):

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Interstitial Lung Disease ◽

Arterial Hypertension ◽

Lung Disease ◽

Pulmonary Arterial

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OP0096 Relevance of the 6-Minute Walking Test in Assessing the Severity of Pulmonary Arterial Hypertension Associated with Systemic Sclerosis, without Interstitial Lung Disease

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2014-eular.1378 ◽

2014 ◽

Vol 73 (Suppl 2) ◽

pp. 97.3-98

Author(s):

S. Sanges ◽

D. Launay ◽

O. Sitbon ◽

E. Hachulla ◽

L. Mouthon ◽

...

Keyword(s):

Systemic Sclerosis ◽

Pulmonary Arterial Hypertension ◽

Interstitial Lung Disease ◽

Arterial Hypertension ◽

Lung Disease ◽

Walking Test ◽

Pulmonary Arterial

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Interstitial lung disease in systemic sclerosis: An HRCT-clinical correlative study

Acta Radiologica ◽

10.1080/j.1600-0455.2003.00058.x ◽

2003 ◽

Vol 44 (3) ◽

pp. 258-264 ◽

Cited By ~ 2

Author(s):

G. C. Ooi ◽

M. Y. Mok ◽

K. W. T. Tsang ◽

Y. Wong ◽

P. L. Khong ◽

...

Keyword(s):

Systemic Sclerosis ◽

Interstitial Lung Disease ◽

Lung Function ◽

Lung Disease ◽

Exercise Tolerance ◽

Forced Expiratory Volume ◽

Diffusion Capacity ◽

Inflammatory Index ◽

Lung Capacity ◽

Hrct Patterns

Purpose: To evaluate high-resolution CT (HRCT) parameters of inflammation and fibrosis in systemic sclerosis (SSc), for correlation with lung function, skin scores and exercise tolerance. Material and Methods: 45 SSc patients (40 women, 48.5±13.4 years), underwent thoracic HRCT, lung function assessment, and modified Rodnan skin scores. Exercise tolerance was also graded. HRCT were scored for extent of 4 HRCT patterns of interstitial lung disease (ILD): ground glass opacification (GGO), reticular, mixed and honeycomb pattern in each lobe. Total HRCT score, inflammation index (GGO and mixed score) and fibrosis index (reticular and honeycomb scores) were correlated with lung function and clinical parameters. Results: ILD was present in 39/45 (86.7%) patients. Abnormal (<80% predicted) forced vital capacity (FVC), total lung capacity (TLC) and carbon monoxide diffusion factor (DLco) were detected in 30%, 22% and 46% of patients. Total HRCT score correlated with FVC ( r=−0.43, p=0.008), FEV1 (forced expiratory volume) ( r=–0.37, p=0.03), TLC ( r=–0.47, p=0.003), and DLCO ( r=–0.43, p=0.008); inflammatory index with DLCO ( r=–0.43, p=0.008) and exercise tolerance ( r=–0.39, p < 0.05); and fibrosis index with FVC ( r=–0.31, p=0.05) and TLC ( r=–0.38, p=0.02). Higher total HRCT score, and inflammation and fibrosis indices were found in patients with abnormal lung function. Conclusion: Qualitative HRCT is able to evaluate inflammation and fibrosis, showing important relationships with diffusion capacity and lung volume, respectively.

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AB0451 TO EVALUATE THE PREVALENCE OF INTERSTITIAL LUNG DISEASE (ILD) AND/OR PULMONARY ARTERIAL HYPERTENSION (PAH) IN PATIENTS AFFECTED BY SYSTEMIC SCLEROSIS (SSC) AND TO DETERMINE THE FACTORS ASSOCIATED WITH ILD

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.3524 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 1253.1-1253

Author(s):

R. Ortega Castro ◽

R. Mariscal-Ocaña ◽

M. Rojas-Giménez ◽

J. Calvo Gutierrez ◽

A. Escudero Contreras ◽

...

Keyword(s):

Systemic Sclerosis ◽

Interstitial Lung Disease ◽

Lung Disease ◽

Topoisomerase I ◽

Systolic Pressure ◽

University Hospital ◽

Pulmonary Artery Systolic Pressure ◽

Skin Involvement ◽

Factors Associated ◽

Anticentromere Antibodies

Background:Systemic sclerosis (SSc) is a chronic autoimmune disease that carries significant mortality. Despite diagnostic and therapeutic advances in recent years, there is still a significant percentage of patients who do not present a complete clinical response, with the associated increase in morbidity and mortality. Specifically, pulmonary disease is frequent and entails a poor prognosis, with interstitial lung disease (ILD) and pulmonary hypertension (PAH) being the two most important complications, the first and second cause of mortality, respectively.Objectives:To evaluate the prevalence of ILD and/or PAH in patients affected by SSc and to determine the factors associated with ILD.Methods:Cross-sectional observational study of 102 patients diagnosed with SSc (Limited, Diffuse, SSc without scleroderma or Pre-scleroderma), treated between 1975 and 2020 at the Reina Sofia University Hospital in Cordoba. A descriptive study of the cohort was carried out and factors independently associated with ILD were evaluated using a multiple logistic regression model.Results:102 patients were included, 87.3% of these were female with an average age of 50.8 (14) years. There were 20 deaths (19.8%), from which 55% died because of SSc and the main reason was ILD and/or PAH. Respiratory complications (as ILD or as PAH) were present in 59 patients (57.8%), of whom 52 were diagnosed with ILD (90.4% with a pattern of non-specific interstitial pneumonia) and 25 PAH, whose mean pulmonary artery systolic pressure was 47.16 (18.54) mmHg. Anti-topoisomerase I antibodies were positive in 34.6% of patients who developed ILD, while anticentromere antibodies were more frequent in SSc without interstitial lung disease (80%). Independent factors associated with ILD were type of SSc, proximal skin involvement, anticentromere antibodies, current treatment with corticoids and the death.Conclusion:Just over half of the patients with SSc have lung disease (as ILD or as PAH). The main risk factors associated with ILD are proximal skin involvement and treatment with glucocorticoids, probably in the context of more severe forms that require more treatment. Anticentromere antibodies are more prevalent in patients with Limited SSc and their expression decreases the risk of developing ILD in these patients.References:[1]Orlandi M, Barsotti S, Lepri G, et al. Clin Exp Rheumatol 2018 Jul-Aug; 36 Suppl 113: 3-23[2]Hao Y, Hudson M, Baron M, et al. Arthritis Rheumatol. 2017;69(5):1067-1077.[3]Furue M, Mitoma C, Mitoma H, et al. Immunol Res. 2017 Aug; 65: 790-7.[4]Nihtyanova SI, Schreiber BE, Ong VH, et al. Arthritis Rheumatol. 2014 Jun; 66: 1625-35.Disclosure of Interests:None declared.

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