Biomarkers in systemic sclerosis-associated interstitial lung disease: review of the literature

Bonhomme, Olivier; Andre, Béatrice; Gester, Fanny; Seny, Dominique de; Moermans, Catherine; Struman, Ingrid; Louis, Renaud; Malaise, Michel; Guiot, Julien

doi:10.1093/rheumatology/kez230

Cited by 64 publications

(87 citation statements)

References 117 publications

(131 reference statements)

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“…[5,7,14] In ILD in the context of autoimmune disorders, alterations to systemic in ammatory parameters like CRP have been frequently reported and also pose a risk factor for the development of pulmonary involvement in such conditions. [28,[34][35][36] Contrary to CRP, we found lactate dehydrogenase (LDH) signi cantly positively correlated with multiple non-in ammatory/ brotic as well as in ammatory HRCT nding scores. Elevations in LDH have been reported in IPF, where they may be associated with functional impairment and have prognostic properties.…”

Section: Discussioncontrasting

confidence: 61%

“…[ [27][28][29] Our nding, that lymphocyte fraction was consistently negatively correlated to HRCT ndings considered "in ammatory" suggests, that similar mechanisms may be present in ILD patients with such phenotype. In BAL however, lymphocyte fraction showed the opposite behavior with distinctly higher values in the presence of GGO and CON, but also NOD and MOS.…”

Section: Discussionmentioning

confidence: 78%

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Computed Tomography Findings as Determinants of Local and Systemic Inflammation Biomarkers in Interstitial Lung Diseases: A Retrospective Cohort Study

Lang¹,

Akbari²,

Hörner³

et al. 2020

Preprint

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Background: Additional to high-resolution computed tomography (HRCT), peripheral blood (PBL) and broncho-alveolar lavage (BAL) could provide biomarkers to distinguish predominantly inflammatory from non-inflammatory/fibrotic interstitial lung disease (ILD) phenotypes. Methods:HRCT of 127 subsequent ILD-board patients were semi-quantitatively evaluated in a standardized way: Reticulation/honeycombing (RET), traction bronchiectasis (TBR) and emphysema (EMP) were classified as non-inflammatory/fibrotic; consolidations (CON), ground glass opacities (GGO), noduli (NDL) and mosaic attenuation (MOS) as active inflammatory findings. These HRCT findings were counted as present or absent in 6 distinct lung regions, resulting scores were graded as minimal (0-1 regions involved), medium (2-4) or extensive (5-6). Associations between routinely assessed PBL/BAL biomarkers with these radiological scores were evaluated using Spearman correlation coefficients; significance of the graded HRCT scores by applying Kruskal-Wallis tests.Results: Blood neutrophil, lymphocyte and eosinophil fraction, neutrophil-lymphocyte ratio (NLR) and BAL lymphocyte fraction consistently showed opposite correlations for inflammatory versus non-inflammatory/fibrotic HRCT finding scores. Blood lymphocyte fraction significantly differed by graded GGO (p=0.032) and CON (p=0.027) extent, eosinophil fraction by TBR (p=0.006) and NLR by CON (p=0.009). C-reactive protein was significantly related to GGO (p=0.023) and CON (p=0.004), BAL lymphocyte fraction to GGO (p=0.017). Conclusions:Blood lymphocyte and eosinophil fraction, NLR, CRP and BAL lymphocyte fraction may aid to differentiate inflammatory from non-inflammatory/fibrotic ILD patterns. Trial registration:This evaluation was based on data from the ILD registry of Kepler University Hospital Linz, as approved by the ethics committee of the federal state of Upper-Austria (EK Nr. I-26-17).

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Section: Discussioncontrasting

confidence: 61%

Section: Discussionmentioning

confidence: 78%

Computed Tomography Findings as Determinants of Local and Systemic Inflammation Biomarkers in Interstitial Lung Diseases: A Retrospective Cohort Study

Lang¹,

Akbari²,

Hörner³

et al. 2020

Preprint

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“…Systemic sclerosis (Ssc) is a rare inflammatory disease of unknown origin associated with multi-organic involvement [1]. The main complication of SSc driving the morbi-mortality of the disease is the particular appearance of interstitial lung disease (ILD) [2].…”

Section: Introductionmentioning

confidence: 99%

A new nucleosomic-based model to identify and diagnose SSc-ILD

et al. 2020

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Background: Systemic sclerosis (SSc) is a rare connective tissue disease associated with rapid evolving interstitial lung disease (SSc-ILD), driving its mortality. Specific biomarkers associated with the evolution of the lung disease are highly needed. We aimed to identify specific biomarkers of SSc-ILD to predict the evolution of the disease. Nucleosomes are stable DNA/protein complexes that are shed into the blood stream making them ideal candidates for biomarkers. Methods: We studied circulating cell-free nucleosomes (cf-nucleosomes) in SSc patients, 31 with ILD (SSc-ILD) and 67 without ILD. We analyzed plasma levels for cf-nucleosomes and investigated whether global circulating nucleosome levels in association with or without other biomarkers of interest for systemic sclerosis or lung fibrosis (e.g., serum growth factors: IGFBP-1 and the MMP enzyme: MMP-9), could be suitable potential biomarkers for the correct identification of SSc-ILD disease. Results: We found that H3.1 nucleosome levels were significantly higher in patients with SSc-ILD compared SSc patients without ILD (p < 0.05) and levels of MMP-9 were significantly increased in patients with SSc-ILD compared to SSc patients without ILD (p < 0.05). Conversely, IGFBP-1 was significantly reduced in patients with SSc-ILD compared to SSc without ILD (p < 0.001). The combination of cf-nucleosomes H3.1 coupled to MMP-9 and IGFBP-1 increased the sensitivity for the differential detection of SSc-ILD. High levels of accuracy were reached with this combined model: its performances are strong with 68.4% of positive predictive value and 77.2% of negative predictive value for 90% of specificity. With our model, we identified a significant negative correlation with FVC % pred (r = −0.22) and TLC % pred (r = −0.31). The value of our model at T1 (baseline) has a predictive power over the Rodnan score at T2 (after 6-18 months), showed by a significant linear regression with R 2 = 19% (p = 0.013). We identified in the sole group of SSc-ILD patients a significant linear regression with a R 2 = 54.4% with the variation of DLCO between T1 and T2 (p < 0.05). Conclusion: In our study, we identified a new blood-based model with nucleosomic biomarker in order to diagnose SSc-ILD in a SSc cohort. This model is correlated with TLC and FVC at baseline and predictive of the skin evolution and the DLCO. Further longitudinal exploration studies should be performed in order to evaluate the potential of such diagnostic and predictive model.

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“…Contrary to what is seen in IPF [12], treatment is mainly based on an aggressive immunosuppressive therapy speci cally proposed in the progressive forms of SSc-ILD. One of the major problem clinicians have to deal with, as in other ILD, is to identify patients at increased risk of progression for early intervention [5,[13][14][15][16]. In this context, biomarkers are highly needed in order to help clinicians for diagnosis, prognosis and the evaluation of the therapeutic response.…”

Section: Introductionmentioning

confidence: 99%

“…The ideal biomarker would be a good predictors in SSc-ILD [14,17]. Although antinuclear antibodies (ANA) were the rst biomarkers available, those biomarkers do not allow for disease activity monitoring [18,19].…”

Section: Introductionmentioning

confidence: 99%

Serum IGFBP-2 in Systemic Sclerosis as a Protective Factor of Lung Dysfunction

Guiot

Njock

Andre

et al. 2020

Preprint

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Background Systemic sclerosis (SSc) is a rare connective tissue disease associated with rapid evolving interstitial lung disease (SSc-ILD), driving its mortality. Specific biomarkers associated with the progression of this lung disease are highly needed. We aimed to identify specific biomarkers of SSc-ILD to predict the evolution of the disease.Methods We compared prospectively serum levels of several biomarkers associated with lung fibrosis in SSc patients (n = 102) compared to healthy subjects (HS) (n = 39). We also performed a longitudinal study in a subgroup of 28 patients analyzing biomarkers variations and pulmonary function tests over a period of 2 years. Furthermore, we performed in vitro analysis to study the impact of Insulin like Growth Factor Binding Protein (IGFBP)-2 on fibrotic activity of human lung fibroblasts.Results Serum levels of IGFBP-1, IGFBP-2, interleukin-8 and matrix metallopeptidase-9 were significantly increased in SSc patients compared to HS while IGF-1 and IGFBP-3 were reduced. The variation of IGFBP-2 between baseline and 2-year follow-up was positively correlated with pulmonary function (assessed by carbon monoxide transfer coefficient (KCO)) at 2-year follow-up (r = 0.6, p < 0.001). Receiver operating characteristic curve analysis enabled us to identify that baseline IGFBP-2 < 105 ng/ml was associated with a better outcome (low risk to display KCO < 70% predicted) at 2-year follow-up (area under the curve = 0.75 at 75% sensibility and 68% specificity, p < 0.05). In vitro functional study showed that IGFBP-2 significantly reduced fibroblast proliferation and pro-fibrotic activity.Conclusions We showed for the first time that serum levels of IGFBP-2 might predict the evolution of SSc-ILD. Baseline IGFBP-2 above 105 ng/ml might be a prognostic factor of alveolo-capillary dysfunction.

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Biomarkers in systemic sclerosis-associated interstitial lung disease: review of the literature

Cited by 64 publications

References 117 publications

Computed Tomography Findings as Determinants of Local and Systemic Inflammation Biomarkers in Interstitial Lung Diseases: A Retrospective Cohort Study

Computed Tomography Findings as Determinants of Local and Systemic Inflammation Biomarkers in Interstitial Lung Diseases: A Retrospective Cohort Study

A new nucleosomic-based model to identify and diagnose SSc-ILD

Serum IGFBP-2 in Systemic Sclerosis as a Protective Factor of Lung Dysfunction

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