2030: Krebs von den Lungen 6 levels (∆KL6) is a reliable marker of disease activity and response to therapy in CTD-ILD

Background/Purpose: Krebs von den Lungen-6 (KL6) is produced by type 2 alveolar epithelial cells. High circulating KL6 levels show a good accuracy in the diagnosis of interstitial lung diseases, including those associated to CTD (CTD-ILD). Increased levels of KL6 have been found to predict mortality in idiopathic pulmonary fibrosis, and also in some cohorts of CTD-ILD patients. Previous data from our prospective CTD-ILD cohort have shown that KL6 changes over time correlate with disease course. Our aim was to evaluate KL-6 sensitivity to change upon different therapeutic interventions

Methods: The study was conducted in CTD-ILD patients included in a multicenter prospective register (NEREA) from Madrid. Demographics and process related variables are recorded and updated with clinical visits (at 6-monthly periods on average). For the aim of the study we selected treatment-naïve incident cases and extracted data regarding underlying disease, date of ILD onset, radiographic patterns, presence of fibrosis at the time of first KL6 determination, FVC (% from reference) and DLco (% from reference). Serum KL-6 concentrations were measured at baseline (_blKL-6) and within the following 6 to 24 months (_fuKL-6). Changes in KL6 levels (∆KL6%) were also determined. Data are shown as mean ± SD. 95% confident intervals (95CI) were calculated to assess the effect size. Statistical analysis included t test, Wilcoxon rank sum and linear regression. Alpha value was set at 0.05.

Results: The study population comprised 57 subjects (84% women), aged 64.7 ± 10.4 years. There were 25 never smokers (44% of the cohort) and only 3 active smokers. Clinical diagnosis included 24 IPAF cases (42%), 12 patients with SSc or related conditions (21%), 4 with RA (7%), and 4 classified as PM/DM (7%), 3 with SS/lupus (5%) and 10 with other autoimmune conditions (17.5%). Radiographic patterns were classified as NSIP in 18 patients (31%), UIP in 22 (39%), and others in 17 (30%). Signs of fibrotic disease were observed in 34 patients (60%). FVC at baseline was 82±21%, while DLco was 64±25%, with 30 patients (53%) showing DLco > 60%. 26 patients (45.6%) remained untreated during the observation period, while 31 patients (54.4%) were put on immunossupressants or/and corticosteroids related to ILD. At baseline, KL-6 levels (_blKL-6) were 2029 ± 2118 IU/ml (median 1512 IU/ml). A second KL6 determination (_fuKL6) was availble at a median of 11.7 (6-12) months of follow-up. Patients treated with immunosuppresants showed a significant reduction in KL6 levels as compared to those remaining untreated (∆KL6_is%: -22.1 ± 38 [95CI: -39.1; -8.2] vs ∆KL6₀: 9.0 ± 46.8 [95CI: -9.9; -27.9], p 0.001). After adjustment by age and sex, treatment with immunosupressants resulted in a risk reduction of KL6 increasing over time (+∆KL6) of 25.9 ± 11.7 [95CI: 2.5; 49.3] vs no treatment (p 0.031). After adjustment for sex and age, treatment initiation was associated with a 22.0 ± 9.7 risk reduction [95CI: 2.7; 41.4] of a +∆KL6

Conclusion: Our results support the role of KL6 as activity biomarker in CTD-ILD, and underscore its value as surrogate marker of reponse to immunosuppresants both in interventional trials and in clinical practice.