Prognostic role of KL-6 in SSc-ILD patients with pleuroparenchymal fibroelastosis.

Krebs von den Lungen-6 (KL-6) is a high-molecular-weight (200kDa) glycoprotein proposed as a diagnostic biomarker for differentiating interstitial lung disease (ILD). Systemic sclerosis (SSc) is a rare immune-mediated disorder, and ILD is the leading cause of morbidity and mortality. Pleuroparenchymal fibroelastosis (PPFE) has been described to have a poor prognosis in SSc-ILD patients. This study undertook to compare serial changes in KL-6 in SSc-ILD patients with and without PPFE, to verify its prognostic value as a disease biomarker. Twenty-five SSc-ILD patients (median IQR, 62 (56-58); 20% males) were retrospectively enrolled. 12 SSc-ILD patients (48%) had also a radiological diagnosis of PPFE. Serum KL-6 concentrations were measured by KL-6 reagent assay (Fujirebio Europe, Ghent, Belgium). Serum KL-6 measurements were increased in SSc-ILD patients with and without PPFE compared with healthy controls (P < .0001). Comparative analysis of the rate of variation of KL-6 over the 6 years of follow-up was performed by serial two-yearly KL-6 measurements: Δ1(t1-t0), Δ2(t2-t1) and Δ3(t3-t2). In SSc-ILD patients with PPFE pattern, Δ3 was significantly different than those without PPFE pattern (P = .0020). Serum KL-6 levels were significantly different (P = .0455) either at Δ2 and Δ3 in the PPFE group. In SSc-ILD patients with PPFE, at t3 serum KL-6 concentrations were inversely correlated with FEV1 (r = -.76; P = .037) and FVC percentages (r = -.79; P = .028). These results suggest that serial measurements of KL-6 in the follow-up of these patients may help to monitor disease progression. In real life, in SSc-ILD patients PPFE should be always evaluated at CT and when present should suggest a tight follow-up to monitor its evolution.

d'Alessandro M ，Bellisai F ，Bergantini L ，Cameli P ，D'Alessandro R ，Mazzei MA ，Gentili F ，Conticini E ，Selvi E ，Frediani B ，Matucci-Cerinic M ，Bargagli E ... -  《-》

Elevated serum Krebs von den Lungen-6 in systemic sclerosis: a marker of lung fibrosis and severity of the disease.

Benyamine A ，Heim X ，Resseguier N ，Bertin D ，Gomez C ，Ebbo M ，Harlé JR ，Kaplanski G ，Rossi P ，Bardin N ，Granel B ... -  《-》

Krebs von den Lungen-6 as biomarker of the new progressive fibrotic phenotype of interstitial lung disease.

Novel progressive fibrotic phenotype has recently been proposed characterized by progressive and inexorable worsening of the disease. Krebs von den Lungen-6 (KL-6) has been proposed as fibrotic-ILD biomarker. We aimed to assess the role of KL-6 in fibrotic-ILD and the progressive phenotype in accordance with serial serum KL-6. 107 patients were enrolled in the study (median age,IQR, 65(54-71)y/o) followed at respiratory diseases and rheumatology units of University of Siena. Thirty-five had diagnoses of IPF, 18 sarcoidosis, 10 PLCH, 5 LAM, 24 fibrotic HP(fHP), 13 RA (4/13 RA-ILD) and 22 SSc (18/22 SSc-ILD). Serial serum samples were collected before therapy (t0) and 24 months later (t1) from IPF, SSc- and RA-ILD patients. Twenty-two healthy controls (HC) were enrolled. Serum samples were assayed for KL-6 concentrations (Fujirebio Europe, Gent, Belgium). Higher KL-6 concentrations were reported in IPF, fHP and SSc-ILD patients than HC (p<0.0001). KL-6 cut-off value of 885 U/mL identified fibrotic-ILD patients. Logistic regression analysis indicated KL-6 (p=0.004) and smoking-habit (p=0.005) affected the ILD diagnosis. The decision tree model showed KL-6>1145 U/mL, DLco≤60.15 %, FVC≤86 % to classify 86 % IPF patients. Inverse correlation between T0-KL-6 and T1-FVC%(r=-0.314, p=0.046) and T1-DLco%(r=-0.327, p=0.038) in the progressive group. KL-6 proved to be a reliable marker for diagnosis and prognosis of fibrotic ILD patients with predictive value in progressive fibrotic patients and a useful marker to identify the new and similar progressive phenotype of IPF and SSc-ILD patients assessing the functional progression in accordance with serial serum KL-6 measurements.

d'Alessandro M ，Conticini E ，Bergantini L ，Mazzei MA ，Bellisai F ，Selvi E ，Cameli P ，Frediani B ，Bargagli E ... -  《-》

Serum levels of Krebs von den Lungen-6 as a promising marker for predicting occurrence and deterioration of systemic sclerosis-associated interstitial lung disease from a Chinese cohort.

A prospective and longitudinal study to investigate the correlations between Krebs von den Lungen-6 (KL-6) serum levels and systemic sclerosis associated with interstitial lung disease (SSc-ILD). Blood samples of baseline and the time point at 2 years follow-up intervals were collected for the measurement of serum KL-6 levels. The baseline clinical, laboratory characteristics, and incidence density of newly diagnosed ILD during the follow up were compared between SSc patients with elevated serum KL-6 levels (KL-6 > 500 U/mL) and those with normal KL-6 levels (KL-6 ≤ 500 U/mL) at baseline. Further, we explored the association between serum KL-6 and deterioration of ILD measured by lung function parameters during follow-up of 2 years. Patients with elevated baseline serum KL-6 had a significant tendency to have disappearance of the finger pad. The incidence density of new-onset ILD in SSc patients with elevated baseline serum KL-6 and those with normal baseline serum KL-6 was 1.33% and 0.51%, respectively. Among the mild lung injury group, the incidence density of ILD deterioration in SSc patients with elevated baseline serum KL-6 and those with normal serum KL-6 was 1.2% and 0.74%, respectively. Serum KL-6 level correlates with the clinical manifestations of microvascular injury. Baseline elevated serum KL-6 may predict deterioration of lung function of SSc-ILD patients with mild lung injury.

Cao XY ，Hu SS ，Xu D ，Li MT ，Wang Q ，Hou Y ，Zeng XF ... -  《-》

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

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. 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. 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). 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.

Elhai M ，Hoffmann-Vold AM ，Avouac J ，Pezet S ，Cauvet A ，Leblond A ，Fretheim H ，Garen T ，Kuwana M ，Molberg Ø ，Allanore Y ... -  《-》