Increased Blood Protein Levels in IPF Tied to Disease Progression | Changes in KL-6 May Predict Progression Risk for Patients: Study

Changes in blood levels of Krebs von den Lungen-6 —  a protein produced by certain lung cells and known as KL-6 — can help predict the risk of disease progression in people with idiopathic pulmonary fibrosis (IPF) who’ve been treated with the anti-fibrotic medicines Esbriet (pirfenidone) and Ofev (nintedanib), a study reported.

Specifically, a 5% or higher increase in KL-6 over the course of one month was considered the best cut-off value to predict disease progression risk.

“Our results showed that changes in KL-6 levels were associated with treatment response to antifibrotic agents in real-world patients with IPF,” the researchers wrote, adding that identifying such changes “might be useful for predicting [disease progression] in patients with IPF receiving antifibrotic therapy when [a starting level of] KL6 is high.”

The study, “Blood Krebs von den Lungen-6 levels predict treatment response to antifibrotic therapy in patients with idiopathic pulmonary fibrosis,” was published in the journal Respiratory Research.

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Trying to better predict disease progression

IPF is a chronic progressive disease of unknown origin characterized by lung tissue scarring. While there is no cure for IPF, anti-fibrotic therapies — in particular Esbriet, marketed by Genentech, and Ofev, sold by Boehringer Ingelheim — have been shown to help lessen tissue scarring.

Both medicines have been linked to reductions in the decline of forced vital capacity (FVC), a key marker of lung function. FVC measures the total amount of air that can be forcibly exhaled from the lungs after a deep breath.

Patients’ responses to these treatments vary markedly, however, with more than 80% showing an absolute decline below 10%.

Biomarkers to assess patients’ responses to anti-fibrotic therapies are key in deciding the next steps in their treatment regimen.

The levels of the protein KL-6 are known to increase when lungs are damaged. Also, an increase of 10% or higher in KL-6 levels has been shown to help identify interstitial lung disease patients at risk of a poorer prognosis.

But whether KL-6 levels also may help predict the risk of disease progression in IPF patients being treated with anti-fibrotic therapies remains unknown.

To answer this, a team led by researchers at the University of Ulsan College of Medicine, in South Korea, conducted a retrospective analysis of 188 patients with IPF. These patients were followed at three hospitals that initiated anti-fibrotic therapy from March 2020 to February 2021.

The mean age of the patients was 68.9 and 77.7% were men. They were followed for a median of  7.6 months after starting anti-fibrotic treatment.

The study’s main goal was to assess disease progression after six months of therapy. Disease progression was defined as a relative decline in FVC of at least 10%, a reduction of at least 15% in diffusing capacity for carbon monoxide (DLCO), acute exacerbation, or death. DLCO measures the ability of the lungs to transfer oxygen from the air to the bloodstream; an acute exacerbation is a sudden worsening of disease symptoms.

Disease progression was seen in 43 patients (22.9%). At the start of follow-up (baseline), those with progressive disease were older (mean age 71.2 vs. 68.3 years), and had lower FVC % predicted (69.1% vs. 76.4%).

The patients with disease progression also walked a shorter distance in the 6-minute walk distance (6MWD) test (377.9 m vs. 447.7 m) compared with those with stable disease. Body mass index (BMI), a measure of body fat, also was lower in patients with progressive disease (23.3 vs. 24.9 kg/m2).

However, no differences were seen at baseline in KL-6 levels between the two groups (1,101.9 vs. 1,021.3 U/mL).

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Krebs von den Lungen-6 protein, KL-6

KL-6 levels linked to disease progression

Researchers then analyzed the outcomes of 77 patients with clinical data on the levels of KL-6 measured over time. In patients with progressive disease, changes in KL-6 levels over the course of one month tended to be more pronounced. Moreover, among those with elevated KL-6 levels at baseline (500 U/mL or higher; 62 patients), changes in KL-6 levels also were greater than in those with stable disease.

Statistical analyses showed that lower BMI and FVC values, as well as a shorter distance in the 6MWD test and elevated KL-6 levels for one month were risk factors for disease progression. Lower BMI and shorter distance in the 6MWD test remained risk factors after researchers made adjustments for age and FVC values.

Also, in patients with elevated baseline KL-6 levels, higher relative changes in KL-6 levels were found to be independently associated with disease progression.

In IPF patients with elevated baseline KL-6 levels, changes in KL-6 over one month were considered statistically good predictors of disease progression.

A 5% increase was deemed the best cut-off value for predicting the risk of disease progression, with a sensitivity of 64.7% and a specificity of 75.6%. Sensitivity is a test’s ability to correctly identify those with a given disease, while specificity refers to its ability to accurately identify those without it.

Patients with a marked increase in KL-6 levels — 5% or higher over one month — were more likely to show disease progression and worsening, as well as a higher decline in FVC values over six months, compared with those without such an increase.

The data also showed that in patients with high KL-6 levels at baseline (total 144), changes in KL-6 levels after one month showed an inverse correlation — when one is high, the other is low — with FVC relative changes over six months.

Overall, these findings suggest that changes in KL-6 levels over one month “might be useful in predicting [disease progression] during antifibrotic treatment and reflect longer-term changes in lung function,” the researchers concluded.