High Level of Chemokine CCL18 Is Associated With Pulmonary Function Deterioration, Lung Fibrosis Progression, and Reduced Survival in Systemic Sclerosis

Hoffmann‐Vold, Anna‐Maria; Tennøe, Anders Heiervang; Garen, Torhild; Midtvedt, Øyvind; Abraityte, Aurelija; Aaløkken, Trond Mogens; Lund, MB; Brunborg, Cathrine; Aukrust, Pål; Ueland, Thor; Molberg, Øyvind

doi:10.1016/j.chest.2016.03.004

Cited by 81 publications

(67 citation statements)

References 29 publications

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“…Previously, small‐sized studies from France and Germany showed that high CCL18 serum levels were associated with a decrease of >10% in the FVC over 4 years and 2 years, respectively . More recently, we observed that high CCL18 serum levels were predictive of a decline in the FVC of >10% . Our study strengthens these previous findings through a larger sample size with more accurate analyses, including multivariate analyses in which other clinical and biologic data as well as other relevant ILD biomarkers were taken into account.…”

Section: Discussionsupporting

confidence: 87%

“…The ultimate goal in utilizing a biomarker is to improve the patient's prognosis, thereby leading to the development of personalized medicine, which is a crucial unmet need in a heterogeneous disease such as SSc. The results of our study validate the CCL‐18 serum level as a strong prognostic biomarker of the worsening of SSc‐associated ILD over a 3‐year period . Previously, small‐sized studies from France and Germany showed that high CCL18 serum levels were associated with a decrease of >10% in the FVC over 4 years and 2 years, respectively .…”

Section: Discussionsupporting

confidence: 81%

“…The extent of fibrosis on baseline and follow‐up HRCTs was measured in a manner as previously described, with results expressed as the percentage of fibrosis based on total lung volume . CT images were reconstructed at a section thickness of 1.25 mm in 10‐mm intervals, and were reviewed in a blinded manner (by ME for the French cohort and by AMHV for the Norwegian cohort), using a simple staging system that was developed by Goh and colleagues .…”

Section: Methodsmentioning

confidence: 99%

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Performance of Candidate Serum Biomarkers for Systemic Sclerosis–Associated Interstitial Lung Disease

Elhaï

Hoffmann‐Vold

Avouac

et al. 2019

Arthritis & Rheumatology

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116

140

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Objective. Interstitial lung disease (ILD) in systemic sclerosis (SSc) runs a highly variable course, and prediction tools are highly desired. The aim of this study was to assess the diagnostic and prognostic performance of 4 candidate serum biomarkers for SSc-associated ILD.Methods. Serum samples from a combined cohort of SSc patients (from Paris, France and Oslo, Norway; n = 427) were analyzed by enzyme-linked immunosorbent assay for concentrations of lung epithelial-derived surfactant protein D (SP-D), Krebs von den Lungen 6 glycoprotein (KL-6), CCL18, and OX40 ligand (OX40L). Lung fibrosis was measured by high-resolution computed tomography and pulmonary function tests. Associations of these candidate biomarkers with baseline disease involvement and prediction of disease progression over time (mean ± SD follow-up 3.2 ± 4.4 years) were investigated.Results. In SSc patients at baseline, serum levels of KL-6 correlated with the forced vital capacity (FVC) (r = −0.317, P < 0.001), diffusing capacity for carbon monoxide (r = −0.335, P < 0.001), and extent of lung fibrosis (r = 0.551, P < 0.001). In multivariate analyses, serum levels of KL-6 and SP-D, but not CCL18 and OX40L, were associated with lung fibrosis (odds ratio [OR] 2.41, 95% confidence interval [95% CI] 1.43-4.07 [P = 0.001] and OR 3.15, 95% CI 1.81-5.48 [P < 0.001], respectively). In SSc patients with ILD at baseline, longitudinal, multivariate analyses showed that CCL18 serum levels were an independent predictor of a >10% decrease in the FVC (hazard ratio [HR] 2.90, 95% CI 1.25-6.73; P = 0.014) and de novo development of extensive disease (HR 3.71, 95% CI 1.02-13.52; P = 0.048). Matrix-based logistic regression models for the diagnosis and prognosis of SSc-associated ILD were constructed, and these models discriminated 3 groups of risk (mild, moderate, or high) for the diagnosis or worsening of lung fibrosis according to the serum levels of SP-D (for diagnosis) and serum levels of CCL18 (for progression of disease).Conclusion. These results show that SP-D is a relevant diagnostic biomarker for SSc-associated ILD, whereas KL-6 could be used to assess the severity of lung fibrosis. CCL18 appears to be a potential predictive marker for progression of ILD in SSc.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 81%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Performance of Candidate Serum Biomarkers for Systemic Sclerosis–Associated Interstitial Lung Disease

Elhaï

Hoffmann‐Vold

Avouac

et al. 2019

Arthritis & Rheumatology

Self Cite

116

140

View full text Add to dashboard Cite

show abstract

“…Furthermore, in an exploratory analysis, we also found that high CCL18 levels at baseline were associated with an increased risk of long‐term mortality due to respiratory failure. These findings substantiate previously published work linking CCL18 with progressive ILD and poor outcomes .…”

Section: Discussionsupporting

confidence: 92%

“…CCL18 is a chemokine that was previously known as pulmonary and activation‐regulated chemokine, and studies have demonstrated higher levels of this chemokine in both serum and bronchoalveolar lavage fluid samples of patients with ILD . Observational studies have demonstrated that CCL18 also predicts various ILD‐related outcomes in SSc .…”

Section: Introductionmentioning

confidence: 99%

Progression of Interstitial Lung Disease in Systemic Sclerosis: The Importance of Pneumoproteins Krebs von den Lungen 6 and CCL18

Kuwana

Charles³

et al. 2019

Arthritis & Rheumatology

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Objective. To investigate the relationship between Krebs von den Lungen 6 (KL-6) and CCL18 levels and the severity and progression of systemic sclerosis (SSc)-related interstitial lung disease (ILD).Methods. Patients enrolled in the Scleroderma Lung Study II (cyclophosphamide [CYC] versus mycophenolate mofetil [MMF]) were included. Baseline and 12-month plasma samples were analyzed by enzyme-linked immunosorbent assay to assess CCL18 and KL-6 levels. The forced vital capacity (FVC) and the diffusing capacity for carbon monoxide (DLco) were measured every 3 months. Joint models were created to investigate the relationship between baseline CCL18 and KL-6 levels and the course of the FVC and DLco over 1 year according to treatment arm.Results. Baseline KL-6 and CCL18 levels each correlated with the extent of radiographic fibrosis. Levels of both CCL18 and KL-6 declined significantly at 1 year. In both treatment arms (n = 71 for CYC, n = 62 for MMF), a higher baseline KL-6 level predicted progression of ILD based on the course of FVC (P = 0.024 for CYC; P = 0.005 for MMF) and DLco (P < 0.001 for CYC; P = 0.004 for MMF) over 1 year. A higher baseline CCL18 level predicted progression of ILD based on the course of the FVC (P < 0.001 for CYC; P = 0.007 for MMF) and DLco (P = 0.001 for CYC; P < 0.001 for MMF) over 1 year, as well as mortality (P = 0.0008 for CYC arm only).Conclusion. In a rigorously conducted clinical trial for SSc-related ILD, KL-6 and CCL18 levels correlated with ILD severity and declined with immunosuppression. Patients with higher baseline KL-6 and CCL18 levels were more likely to experience disease progression despite treatment. KL-6 and CCL18 levels could be used to identify patients with a progressive ILD phenotype who may benefit from a more aggressive initial treatment approach.

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Combining Clinical and Biological Data to Predict Progressive Pulmonary Fibrosis in Patients With Systemic Sclerosis Despite Immunomodulatory Therapy

Volkmann,

Wilhalme,

Assassi

et al. 2023

ACR Open Rheumatology

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ObjectiveProgressive pulmonary fibrosis (PPF) is the leading cause of death in systemic sclerosis (SSc). This study aimed to develop a clinical prediction nomogram using clinical and biological data to assess risk of PPF among patients receiving treatment of SSc‐related interstitial lung disease (SSc‐ILD).MethodsPatients with SSc‐ILD who participated in the Scleroderma Lung Study II (SLS II) were randomized to treatment with either mycophenolate mofetil (MMF) or cyclophosphamide (CYC). Clinical and biological parameters were analyzed using univariable and multivariable logistic regression, and a nomogram was created to assess the risk of PPF and validated by bootstrap resampling.ResultsAmong 112 participants with follow‐up data, 22 (19.6%) met criteria for PPF between 12 and 24 months. An equal proportion of patients randomized to CYC (n = 11 of 56) and mycophenolate mofetil (n = 11 of 56) developed PPF. The baseline severity of ILD was similar for patients who did, compared to those who did not, experience PPF in terms of their baseline forced vital capacity percent predicted, diffusing capacity for carbon monoxide percent predicted, and quantitative radiological extent of ILD. Predictors in the nomogram included sex, baseline CXCL4 level, and baseline gastrointestinal reflux score. The nomogram demonstrated moderate discrimination in estimating the risk of PPF, with a C‐index of 0.72 (95% confidence interval 0.60‐0.84).ConclusionThe SLS II data set provided a unique opportunity to investigate predictors of PPF and develop a nomogram to help clinicians identify patients with SSc‐ILD who require closer monitoring while on therapy and potentially an alternative treatment approach. This nomogram warrants external validation in other SSc‐ILD cohorts to confirm its predictive power.

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High Level of Chemokine CCL18 Is Associated With Pulmonary Function Deterioration, Lung Fibrosis Progression, and Reduced Survival in Systemic Sclerosis

Cited by 81 publications

References 29 publications

Performance of Candidate Serum Biomarkers for Systemic Sclerosis–Associated Interstitial Lung Disease

Performance of Candidate Serum Biomarkers for Systemic Sclerosis–Associated Interstitial Lung Disease

Progression of Interstitial Lung Disease in Systemic Sclerosis: The Importance of Pneumoproteins Krebs von den Lungen 6 and CCL18

Combining Clinical and Biological Data to Predict Progressive Pulmonary Fibrosis in Patients With Systemic Sclerosis Despite Immunomodulatory Therapy

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