Krebs von den Lungen-6 as biomarker of the new progressive fibrotic phenotype of Interstitial Lung Disease

One of the most common types of idiopathic interstitial diseases (ILD) is idiopathic pulmonary fibrosis (IPF), which exhibits a progressive clinical course interrupted occasionally by high mortality events, known as acute exacerbations. According to recent research, patients with non-IPF ILDs, such as hypersensitivity pneumonitis (HP) and connective tissue disorders associated with ILD (CTD-ILD), as well as patients with non-IPF ILDs, may experience progressive deterioration regardless of the treatment they receive. Further, several recent studies have found that IPF and non-IPF ILDs exhibit similar pathogenic pathways, such as shortening of telomeres, dysfunction of epithelial cells, and dysregulation of the immune system. Considering these factors, a novel progressive fibrotic phenotype has recently been proposed, which includes all ILD patients (both asymptomatic and asymptomatic) who show a progressive and inexorable worsening of the disease. ILD patients have not yet been able to benefit from a single validated bioindicator that can be routinely used in clinical management. There have been numerous studies demonstrating the prognostic value of Krebs von den Lungen-6 (KL-6), a glycoprotein with a high molecular weight produced by damaged or regenerating pneumocyte type II. This study aimed to determine the role of KL-6 as a diagnostic and prognostic marker of fibrotic ILD. A primary objective of this study was to compare KL-6 concentrations at the time of diagnosis and prior to any pharmacological treatment in patients with IPF, fibrotic HP, LAM, PLCH, sarcoidosis, RA, and SSc with and without ILD. Secondly, we evaluated the functional progression of patients with IPF, RA- and SSc-ILD based on serial concentrations of KL-6 in their serum. A total of 107 patients were enrolled in the study (median age IQR, 65 (54-71) years) who were being monitored at Siena University Hospital's Rheumatology Unit and Sarcoidosis and Interstitial Lung Disease Referral Centre. Thirty-five had diagnoses of IPF (median age IQR, 69 (63-76) years; 26 males), 18 sarcoidosis (median age IQR, 53 (48-63) years; 2 males), 10 PLCH (median age IQR, 55 (51-68) years; 3 males), 5 LAM (median age IQR, 43 (41-45) years; one male), 24 fibrotic HP (median age IQR, 70 (65-74) years; 13 males). Among rheumatologic diseases, thirteen patients had diagnoses of RA (median age IQR, 66 (59-68) years; 2 males) and 4 out of 13 had ILD involvement. Twenty-two had diagnoses of SSc (median age IQR, 64 (57-68) years; 4 males). Eighteen out of 22 had ILD involvement and 10 out of 18 revealed radiological diagnosis of PPFE. Serial serum samples were collected before therapy started (t0) and 24 months later (t1) from patients with IPF, SSc- and RA-ILD. LFT parameters were repeated according to our center's follow-up protocol and performed in accordance with ATS/ERS guidelines. We also enrolled 22 healthy controls (median age (IQR) 54 years (42-60); 6 males). A growing understanding of IPF's pathophysiology has led to the development of numerous anti-fibrotic therapies. At the present time, only two treatments are approved for treatment of this disease (pirfenidone and nintedanib), and both are of limited efficacy. As a reliable marker for diagnosing and prognosing fibrotic ILD patients, KL-6 also proved to have predictive value in patients with progressive fibrotic diseases. In accordance with serial serum KL-6 measurements, IPF and SSc-ILD patients can be identified as having a similar progressive phenotype as identified by serial KL-6 measurements.