Turnover Of Type I And III Collagen For The Prediction Of Idiopathic Pulmonary Fibrosis Progression

Background

IPF (Idiopathic pulmonary fibrosis) is characterized by an accumulation of the fibrillar collagen in alveolar spaces resulting in the reduced pulmonary functions and a higher risk of mortality. Biomarkers for measuring the turnover of collagen types I and III might provide key information needed for predicting the prognosis of IPF and influence the treatment decisions.

Methods

Several serological biomarkers that reflect the formation of PRO-C3 (type III collagen) and C1M (degradation of type I) and C3M (III collagen) were assessed in a cohort of 178 patients newly diagnosed with IPF. The clinical data and blood samples were collected at the baseline, 6, and 12 months.?

The longitudinal and baseline biomarker levels were correlated to the progression of IPF defined as more than 4% decline in the FVC (forced vital capacity) and/or more than 9% decline in the DLco (diffusing capacity for carbon monoxide) within or without an all-cause mortality in the 12 month period.?

Furthermore, the differences in the change of the biomarker levels between the patients receiving antifibrotic drugs were also analyzed.

Background

IPF (idiopathic pulmonary fibrosis) is characterized by unknown aetiological factors and poor prognosis. The heterogeneous rate of progression of this disease further complicates the prediction of the future course for most patients. The antifibrotic drugs approved for the management of this condition, nintedanib, and pirfenidone, are shown to control the decline in the FVC (forced vital capacity) as compared to a placebo.?

But, the curative treatment for IPF is believed to be only lung transplantation, though the timely referral or identification of the eligible patients could be a challenge. From the perspective of the management of IPF, the unfulfilled clinical needs are the requirements that can help to distinguish the patients with a more stable disease form from those at a higher risk of faster progression.?

The GAP (gender, age, and physiology) index was indicated for the prediction of mortality, though it was not the predictor for the physiological progression. Hence, biomarkers that can identify the patients at a higher risk of progression and stratifying the patients into relevant groups who are more likely to benefit from the antifibrotic therapy could be valuable tools.

Discussion

In patients diagnosed with IPF, the measurement of the levels of the serum biomarkers for type I and III collagen turnover at the time of the diagnosis could be related to the disease progression within 1 year. Moreover, it was demonstrated that the longitudinal level of collagen type I and III turnovers could help to distinguish the patients with a progressive form of this disease, though no change in the collagen turnover biomarkers could be detected in the patients who were treated with antifibrotics.

Collagen type I and III are found in the interstitial matrix. These are the essential components of the lungs as they provide tensile strength to alveolar interstitium. IPF may result from the increase in the levels of the interstitial collagen that changes the architecture of the small airspaces in the lung tissues. The elevated collagen turnover has also been shown to be linked to disease progression in patients with IPF.?

This study has demonstrated that the degradation and formation of type III collagen could be associated with a higher disease severity at the baseline and the high levels of PRO-C3 could be related to better chances of survival. In this study, we investigated if the biomarkers of collagen turnover measured at the baseline could help to predict the risk of disease progression.?

When the odds ratios in the IPF patients were calculated, it was found that the patients who belonged to the upper and middle tertiles of PRO-C3 or C1M had a relatively higher risk of faster disease progression than the patients in the low baseline tertile. This suggests that measuring the formation of collagen type III and degradation of collagen type I at the baseline could help in identifying the patients at the risk of progression and help the clinicians in the treatment choices.?

Currently, there are no biomarkers or clinical scores that can help to predict and identify the disease progression in patients with IPF treated with the antifibrotic drugs. The findings of this study have suggested that the future studies related to the collagen turnover could serve as the prognostic biomarkers in the IPF patients.?

A previous study has examined whether some biomarkers (CCL18, CXCL13, CCL13, COMP, YKL40and periostin) measured at the baseline in the ASCEND and CAPACITY trials could help in the prediction of the FVC changes in the patients treated with pirfenidone. No association was found between the levels of the baseline biomarkers and a change in FVC in patients who were treated with pirfenidone. The common limitation in these biomarker studies was the absence of comparison between the prognostic performances of different biomarkers.?

As the data from this study suggested that patients with the higher baseline collagen turnover are at a higher risk of faster disease progression, it will be interesting to make the direct comparisons of? PRO-C3 and C1M with the other biomarkers mentioned above for verifying whether they can perform better.

Interestingly, recent studies have also shown that the degradation of collagen type III could be related to the disease severity during diagnosis. But, the present analyses showed that it was not linked to the increased risk of progression, suggesting that collagen type III is more likely to be associated with the disease severity instead of just being a prognostic biomarker. Also, previous studies have indicated that C3M might be a prognostic biomarker in the patients with a progressive form of this disease.

Finally, the percentage change from the baseline of collagen turnover was also compared in patients who were treated with the antifibrotic therapy and those who were not.?

Surprisingly, no differences were found in the biomarker levels. Furthermore, no differences in the biomarker levels were found between the patients who were treated with pirfenidone or nintedanib. This indicated that collagen type I and III turnover may not be influenced by the antifibrotic treatment.?

However, these results need to be re-confirmed through other studies that include a broader group of patients without any active treatment. Patients who do not receive antifibrotic therapy in this study were the highly selected group in the higher age group and a shorter 6MWT distance as compared to the patients who were treated with the antifibrotic therapy.? This could have influenced the results potentially.?

However, the results are similar to those of the INMARK study wherein C3M and C1M were found to be left unmodulated by treatment with nintedanib. The patients in the INMARK study and PFBIO cohort had a mild form of the disease. But, the placebo group in INMARK study had shown a decline in the FVC, while some patients from PFBIO cohort had a stable FVC over a period of 12 months.?

In contrast to nintedanib and pirfenidone, it was also shown in a study that the treatment with omipalisib in patients with IPF reduced the level of formation of type III collagen. The antifibrotic treatment could have had a different mechanism of action when compared to pirfenidone and nintedanib, and it would be interesting to consider the combinations of these antifibrotics, each targeting a different pathway of fibrotic cascade.

In conclusion, collagen type I and III turnovers assessed at the time of the diagnosis of IPF could be related to the disease progression within 1 year. Moreover, the longitudinal levels of collagen turnover might help to distinguish the patients with IPF having a progressive form of the disease from the patients with a stable form.?

This might provide key information to the clinicians to help them identify patients at a higher risk of faster disease progression. In addition, the treatment with antifibrotics like nintedanib and pirfenidone may not affect the serum biomarkers of collagen type I and III turnovers in these patients.

Results

The increase in the baseline level of biomarkers for the type I and III collagen turnover were associated with a higher risk of disease progression within twelve months compared to the patients having a lower baseline turnover of type I and III collagen.?

Conclusion

The baseline levels of collagen type I and III turnovers could be associated with a faster disease progression in a 12 month period. The levels of the longitudinal biomarkers of collagen type I and III turnover could also be related to the progressive form of this disease.?

Moreover, therapy with antifibrotics was not found to affect the collagen turnover biomarkers in patients with IPF. C1M and PRO-C3 might be potential biomarkers for the progressive disease behaviors in IPF.