Background/Purpose: Krebs von den Lungen-6 (KL6) is a mucin-1 glycoprotein produced by type 2 alveolar epithelial cells , which increase at peripheral blood show a good accuracy in the diagnosis of interstitial lung diseases, including those associated to connective tissue diseases (CTD-ILD). Some studies have explored the role of KL6 as a biomarker of mortality or of a fibrosing progressive phenotype (FPP) in CTD-ILD cohorts, with conflicting results. KL6 levels have been found to drop after response to treatment in patients with rapidly progressive ILD forms. In this regard, we have postulated that KL6 changes over time might be a better predictor of FPP in patients with CTD-ILD than baseline levels. Our aim was to evaluate the clinical relevance of both of KL6 baseline levels and its changes (∆KL6) in relationship with functional deterioration in a prospective cohort of CTD-ILD patients

Methods: The study was conducted in CTD-ILD patients enrolled in a prospective register (NEREA). We extracted data regarding underlying disease, date of ILD onset, radiographic patterns, presence of fibrosis at the time of first KL6 determination, forced vital capacity (FVC) and carbon monoxide diffusing capacity (DLco). A FPP was defined by a ≥10% decline in FVC at 12 or 24 mths from baseline. Serum KL6 concentration was measured with Lumipulse. Data are expressed in mean ± SD. Two sample t tests, Pearson’s R and logistic regression were used for the analysis.

Results: The study population comprised 188 subjects (69% women) aged 64,6 ± 11,6 yr. Ninety eight patients (52%) had new-onset ILD. Clinical diagnosis included 66p diagnosed with IPAF, 40 SSc or related conditions, 29 RA, 15 IIM, 11 SS and 26 other autoimmune conditions. At baseline, FVC was 82.8 ± 20.6 %; DLco was 64.6 ± 23.1% and KL6 levels (_blKL6) were 1450 ± 1525 IU/ml. KL6 was higher in new-onset ILD cases (p 0.016), slightly higher in women (ns) as also in non-fibrotic ILD (ns), while they did not associate with age. There was a significant inverse correlation between _blKL6 and functional respiratory tests (p 0.002, and p 0.0025, respectively). In 102 patients, there was a second KL6 determination (_fuKL6) within the following 9 months after baseline. The relative ∆KL6 ([_fuKL6-_blKL6]/_blKL6)% in the whole population was 1.2 ± 37.9% (while raw ∆KL6 was 366 ± 1617 IU/ml). 

Incident cases showed a higher decrease in ∆KL6 as compared to prevalent (p 0.001) and non-fibrotic than fibrotic ones (p 0.02). There were 24p showing a > 10% decline in FVC at 12 or 24 mths of follow-up, therefore representing an FPP. While those patients with stable disease had a relative ∆KL6 of -6.0 ± 34.1%, FPP cases showed a ∆KL6 of 14.4 ± 45.8% (p 0.021). Risk of progression was associated with relative ∆KL6 after adjusting by age, sex, radiographic patterns, clinical diagnosis and functional status at baseline (p 0.019).

Conclusion: Our results point to ∆KL6 as a better predictor of a fibrotic progression in patients with CTD-ILD than baseline KL6 levels. A drop in KL6 values differentiated between stable and fibrosing progressive cases at 1 and 2 years and may account for an early surrogate marker of treatment efficacy in clinical practice and/or research.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/changes-in-krebs-von-den-lungen-6-levels-%e2%88%86kl6-predict-fibrosing-progression-of-interstitial-lung-disease-in-patients-with-an-underlying-connective-tissue-disease-ctd-ild/