Patients with idiopathic pulmonary fibrosis (IPF) display an unpredictable and heterogeneous disease behaviour with a progressive functional decline towards respiratory failure.1 In the last few years, score systems have been developed to assess the disease progression; however, they have shown limited value in predicting disease outcome at the time of diagnosis.2,3 Among molecular biomarkers, short leukocyte telomere length (LTL) is considered a risk factor for the development of IPF and it has been linked to worse transplant-free survival in untreated patients.4 Antifibrotics have proven effective in slowing down the rate of functional decline and disease progression of IPF.5 However, a significant variability in treatment response still exists,6 and it remains unclear whether TL contributes to such variable response to treatment in patients
The study investigated whether TL correlates with functional decline and survival in a phenotypically well-defined population of IPF patients treated with antifibrotic drugs (nintedanib or pirfenidone).
Telomere length was measured by real-time PCR in genomic DNA extracted from peripheral blood leukocytes in 105 consecutive patients with a diagnosis of IPF who started therapy (either with pirfenidone or nintedanib equally distributed). Data were expressed as number of telomere repeats (T) normalised to single copy reference gene β-globin (S) and results were expressed as T/S ratio. Twenty-three healthy well-matched individuals served as controls. A subsequent analysis was conducted after the first year of therapy in 28 subjects and after 3 years in 17 subjects. The authors categorised patients as stable or decliners based on the forced vital capacity decline in the first year of therapy (<5% or >5%, respectively).
Demographic characteristics of the whole population, at baseline, reflect a typical patient with IPF (male and former smoker) and the functional profile reflects a mild disease. The study revealed that IPF patients had shorter TL compared to healthy matched controls (1.26±0.34 versus 1.64±0.53; p=0.002). The probability of survival according to TL was explored, and when the data analyses was limited to TL at baseline <10%, 25%, and 50%, no significant differences in terms of survival were observed. In summary, LTL at T0 did not predict a survival difference in treated patients. Additionally, IPF patients were separated as stable (n=19) and decliners (n=9), who displayed similar demographics and functional characteristics but different forced vital capacity decline after 1 year of treatment. TL at baseline in stable patients and decliners was then compared; however, no significant difference was observed (1.19±0.25 versus 1.24±0.29, respectively; p=0.46) suggesting that the different treatment response occur regardless if TL is at baseline. Analysis of TL dynamics and functional trajectory in treated patient with IPF-1 year (n=28) displayed no significant change (p=nonsignificant) suggesting the potential influence of treatment on the attrition rate of telomere shortening. Similarly, in the subgroup of 17 patients out of 105 who were treated up to 3 years, TL did not change significantly. A strong correlation was found between TL at baseline and telomere attrition rate from baseline up to the third year (r=-0.7; p=0.001); therefore, individuals with longer telomeres at baseline experience the largest telomere attrition rates over time.
TL at baseline is associated neither with the rate of functional decline over time nor with survival in IPF patients on antifibrotic therapy. The rate of LTL shortening over time correlates strongly with LTL at baseline. Further studies are needed to clarify whether antifibrotic therapy slows down disease progression by reducing telomere shortening.