Serum markers of pulmonary epithelial damage in systemic sclerosis‐associated interstitial lung disease and disease progression

Stock, Carmel; Hoyles, Rachel; Daccord, Cécile; Kokosi, Maria; Visca, Dina; Lauretis, Angelo De; Alfieri, Veronica; Kouranos, Vasilis; Margaritopoulos, George; George, Peter M.; Molyneaux, Philip L.; Chua, Felix; Maher, Toby M.; Abraham, David; Ong, Voon H; Donovan, Jackie; Sestini, Piersante; Denton, Christopher P.; Wells, Adrian; Renzoni, Elisabetta

doi:10.1111/resp.13988

Cited by 36 publications

(32 citation statements)

References 25 publications

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“…The results of previous studies suggest that KL-6 levels > 1273 U/ml at baseline are associated with disease progression, or "end-stage lung disease" [12,21]. However, the baseline KL-6 levels were not associated with disease progression in our study.…”

Section: Discussioncontrasting

confidence: 82%

“…In the cohort study of Kuwana et al, the mean FVC predicted was 83.7%, and the DLco predicted was 55.6% [12]. In the retrospective/prospective cohort study of Stock et al, the median FVC predicted values were 80.1%/73.8% and the median DLco predicted values were 55.5%/39.9% [21]. The parameters of lung function in those cohorts were worse than the parameters in our cohort, which showed a median FVC predicted of 88.0% and DLco predicted of 57.5% at baseline in the patients with progressive disease.…”

Section: Discussionmentioning

confidence: 95%

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Kinetic Changes in Serum KL-6 Levels Predict Disease Progression in Patients with Systemic Sclerosis-Associated Interstitial Lung Disease: A Retrospective Observational Study

Watanabe

Kase

Saeki

et al. 2021

Preprint

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Background: The clinical course of patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable. The Krebs von den Lungen-6 (KL-6) glycoprotein is a promising biomarker for reflectingepithelial injury. However, serum KL-6 and its association with the progression of SSc-ILD have been understudied. Methods: We reviewed 77 consecutive patients with SSc-ILD seen from 2004 to 2016. A longitudinal study of forced vital capacity (FVC), serum KL-6 levels, and the changes in KL-6 levels from baseline (ΔKL-6) was conducted. The progression of ILD was defined as ≥10% relative decline in FVC predicted or 5%–10% decline in FVC predicted along with radiological progression on chest computed tomography. The risk factors for ILD progression were assessed by univariate and multivariate regression.Results: The 77 study patients included 58 women (75%). The median age of the study patients was 56 years, and 59 (79%) patients had diffuse cutaneous SSc. During a 5-year follow-up period, 10 (13%) showed rapid progression of ILD within 2 years, 39 (51%) had overall progressionduring the 5 years, and 28 (36%) had stable disease. Most patients with progressive ILD showed elevationsin serum KL-6 levels over the initial 1-year follow-up period. The best cut-off value for ΔKL-6 that predicted progression of ILD was 193 U/mL (sensitivity 81.6%, specificity 92.9%). Multivariate analysis with adjustment revealed that diffuse cutaneous SSc(hazard ratio [HR] 3.1; 95% confidence interval [CI] 1.05-9.36]) and ΔKL-6 > 193 U/mL from baseline(HR, 4.7; 95% CI, 2.14-10.4)were independent predictors for progression of SSc-ILD.Conclusion: Changes in the KL-6 level can be useful for predicting disease progression in patients withSSc-ILD.

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Section: Discussioncontrasting

confidence: 82%

Section: Discussionmentioning

confidence: 95%

Kinetic Changes in Serum KL-6 Levels Predict Disease Progression in Patients with Systemic Sclerosis-Associated Interstitial Lung Disease: A Retrospective Observational Study

Watanabe

Kase

Saeki

et al. 2021

Preprint

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“…Serum samples for assay of the following proteins/oncomarkers were drawn at baseline t0 and every 6 months of follow-up (6 months (t1), 12 months (t2), 18 months (t3), and 24 months (t4)): chitotriosidase (chitinase-1), carcinoembryonic antigen (CEA), cancer antigen 15-5 (Ca15-3), neuron-specific enolase (NSE), cancer antigen 19-9 (Ca19-9), cytokeratin fragment 21-1 (Cyfra 21.1), and cancer antigen 125 (Ca-125). Oncomarkers and chitotriosidase were assayed as previously reported [7,8,10,23,39,42,43].…”

Section: Methodsmentioning

confidence: 99%

Systematic Review and Metanalysis of Oncomarkers in IPF Patients and Serial Changes of Oncomarkers in a Prospective Italian Real-Life Case Series

d’Alessandro

Bergantini

Torricelli

et al. 2021

Cancers

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Background: Idiopathic pulmonary fibrosis (IPF) is a severe progressive interstitial lung disease. At 5-year follow-up, 15% of IPF patients develop lung cancer, which significantly reduces the survival rate. Here we review the literature on the clinical role of oncomarkers in IPF progression, and describe the trend of routine oncomarkers in IPF patients over the longest follow-up yet reported. Materials and methods: A systematic search of the literature in PubMed was performed to find relevant studies published up to 24 September 2020. The most common oncomarkers were chosen to select papers related to pulmonary fibrosis. Then, 24 IPF patients and 25 non-IPF patients, followed at Careggi ILD Referral Centre and Siena Regional Referral Centre for ILD, were enrolled consecutively. Results: A few studies reported an association between serum oncomarkers and severity of IPF. NSE, CEA, Ca19.9, and Ca125 were higher in the IPF, than in the non-IPF, group at every follow-up (p < 0.05). Ca15.3 concentrations were higher in the IPF, than the non-IPF, group at t3 (p = 0.0080) and t4 (p = 0.0168). To improve the specificity and sensitivity of Ca15.3, a panel of biomarkers was analyzed, with the IPF group as dependent variable, and chitotriosidase, Cyfra 21.1, Ca15.3, Ca125, and Ca19.9 as independent variables. Conclusions: This study focused on the discovery of multiple biomarker signatures, such as combinations of oncomarkers, that are widely and routinely available in biochemistry laboratories. The combination of clinical parameters and biological markers could help achieve more accurate results regarding prognosis and response to treatment in IPF. Our results could pave the way for a more “personalized” medical approach to patients affected by IPF.

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“…In fact, it is considered as a useful marker of epithelial lung damage and a predictor of fibrotic progression in these diseases 6 – 17 . In addition, the functional polymorphism rs4072037, located at nucleotide position 568 in the exon 2 of MUC1 gene, affects serum KL-6 levels 9 , 14 , 18 – 21 . An association between MUC1 rs4072037 and diverse pathologies has also been reported 21 – 24 .…”

Section: Introductionmentioning

confidence: 99%

Role of MUC1 rs4072037 polymorphism and serum KL-6 levels in patients with antisynthetase syndrome

Remuzgo‐Martínez

Atienza‐Mateo

Ocejo-Vinyals

et al. 2021

Sci Rep

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Mucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD +) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD +), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T > C. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.

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Serum markers of pulmonary epithelial damage in systemic sclerosis‐associated interstitial lung disease and disease progression

Cited by 36 publications

References 25 publications

Kinetic Changes in Serum KL-6 Levels Predict Disease Progression in Patients with Systemic Sclerosis-Associated Interstitial Lung Disease: A Retrospective Observational Study

Kinetic Changes in Serum KL-6 Levels Predict Disease Progression in Patients with Systemic Sclerosis-Associated Interstitial Lung Disease: A Retrospective Observational Study

Systematic Review and Metanalysis of Oncomarkers in IPF Patients and Serial Changes of Oncomarkers in a Prospective Italian Real-Life Case Series

Role of MUC1 rs4072037 polymorphism and serum KL-6 levels in patients with antisynthetase syndrome

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