Our study reported the association between serum KL-6 levels and disease progression in patients with SSc-ILD over a long follow-up period. The increase in serum KL-6 levels and decrease in FVC values occurred simultaneously. To the best of our knowledge, this is the first study to show the utility of kinetic changes in KL-6 levels for monitoring disease progression in patients with SSc-ILD.
Serum KL-6 levels reflect disease progression in patients with SSc-ILD. In our cohort of 77 patients, around 64% showed progression of SSc-ILD at any time over the 5-year follow-up period, and 36% did not show decrease in FVC. Of the patients who progressed, 13% showed rapid and continuous decreases in their FVC values. The progression patterns were consistent with those of previous studies [4, 6]. Longitudinal analysis of the FVC values and serum KL-6 levels showed that the increase in KL-6 levels appeared mostly at the time of the decrease in FVC values. Since the course of SSc-ILD is highly variable and heterogeneous, baseline serum KL-6 levels or a single measurement of the KL-6 level during follow-up are unable to predict changes in FVC . Furthermore, a change in the KL-6 level from baseline was an independent significant predictor for decrease in FVC over a 5-year follow-up period. These findings are similar to those in patients with idiopathic pulmonary fibrosis: serial increases in serum KL-6 levels have been associated with poor survival .
The results of previous studies suggest that KL-6 levels > 1273 U/ml at baseline are associated with disease progression, or “end-stage lung disease” [12, 21]. However, the baseline KL-6 levels were not associated with disease progression in our study. This discrepancy may be accounted for by differences in the disease severity of patients at baseline. In the cohort study of Kuwana et al, the mean FVC predicted was 83.7%, and the DLco predicted was 55.6% . In the retrospective/prospective cohort study of Stock et al, the median FVC predicted values were 80.1%/73.8% and the median DLco predicted values were 55.5%/39.9% . The parameters of lung function in those cohorts were worse than the parameters in our cohort, which showed a median FVC predicted of 88.0% and DLco predicted of 57.5% at baseline in the patients with progressive disease. Moreover, the mean KL-6 levels of the patients from the retrospective/prospective cohort study of Stock et al were 2189 U/mL in patients with end-stage lung disease and 1679 U/mL in those with extensive disease, which is much higher compared to the levels seen our cohort, which included the median KL-6 level of 841 U/mL in our patients with progressive disease. Thus, our cohort consisted of patients with relatively mild to moderate disease with normal lung function and low KL-6 levels at baseline.
The results of our study indicate an association between KL-6 levels and disease progression in patients with SSc-ILD. Although the pathogenesis of SSc-ILD has not been fully investigated, repetitive epithelial and endothelial cell injury is believed to be a first step in pathological process. This leads to activation of the innate and adaptive immune system, differentiation of fibroblasts to a myofibroblast phenotype, with accumulation of extracellular matrix and development of pulmonary [22, 23]. KL-6 is expressed more prominently by proliferating, regenerating, or injured type II cells than by uninjured type II cells, and may leak into the circulation after damage to lung epithelium . Thus, KL-6 is likely to reflect the initial worsening of lung function instead of predicting long-term survival.
The limitation of this study is that it is a retrospective and single-institution study of a small number of patients with relatively mild SSc-ILD. The timing of pulmonary function testing varied, which could have led to an underestimation of disease progression. However, the strength of this study is the detailed analysis of the association between longitudinal serum KL-6 levels and progression of SSc-ILD. KL-6 has been available for routine clinical use in Japan. Additional multicenter prospective studies are needed to confirm the utility of serial changes in KL-6 for monitoring patients with SSc-ILD.
In conclusion, kinetic change in KL-6 levels is useful for the prediction of disease progression in patients with SSc-ILD. Serial monitoring of serum KL-6 levels in relation to baseline indices may provide additional prognostic information, even when results of repeated pulmonary function tests are unavailable. The results can also be helpful for deciding on the types and timing of treatments such as antifibrotic agents for patients with SSc-ILD.