OBJECTIVES: Several studies have explored the role of Krebs von den Lungen-6 (KL-6) as a biomarker in diagnosing connective tissue diseases associated with interstitial lung disease (CTD-ILD). Chest high-resolution computed tomography is the gold standard for ILD diagnosis, but costs and ionizing radiation may limit its use in clinical practice. We conducted a meta-analysis to assess the clinical significance of KL-6 as a biomarker in patients with CTD-ILD when compared to patients with CTD non-ILD and healthy controls (HC).

METHODS: Comprehensive searches of electronic databases, including MEDLINE, Google Scholar, and Cochrane Library were conducted till December 25^th, 2023. Studies were screened based on a pre-specified protocol. A meta-analysis evaluating the impact of KL-6 biomarker was conducted using a random-effects model (REM) as a priori. The impact of heterogeneity was evaluated through sensitivity and subgroup analyses. Impact of outlier studies was assessed using leave-one study out analysis and Galbraith plot.

RESULTS: Twenty studies evaluating 1562 patients with CTD-ILD, 542 patients with CTD non-ILD and 581 HC met the inclusion criteria. In a REM, the overall pooled mean difference (MD) showed clinically significantly (>500 IU/ml) higher KL-6 when comparing CTD-ILD with CTD non-ILD [MD:728.04, 95%CI:536.17-919.92, I²=96.35%, p=0.001] and CTD-ILD with HC [MD:795.32, 95%CI:568.72-1021.93, I²=98.55%, p=0.001]. Although statistical heterogeneity was high (I²>90%), individual study MDs were directionally aligned with the pooled estimate. A subgroup analysis of studies by study design, study population, region, and biomarker test showed consistent findings aligned with the base case meta-analysis. Assessments of clinical, and statistical heterogeneity indicated the meta-analysis was robust. No publication bias was observed.

CONCLUSIONS: Clinically significantly higher KL-6 levels were observed in CTD-ILD patients compared to CTD non ILD and HC. KL-6 serves as a prominent option for early detection and management of ILD which can reduce the progression of disease and economic burden in patients with CTD-ILD.