Molecular imaging for systemic sclerosis-interstitial lung disease

The evolution of interstitial lung disease (ILD) varies among patients with systemic sclerosis with some patients exhibiting disease stability, even in the absence of therapy, and others exhibiting a rapid decline in lung function, despite therapy.¹ Predicting the course of ILD in systemic sclerosis is an ongoing area of research, because understanding progression risk can help guide therapeutic decision making. In The Lancet Rheumatology, Christina Bergmann and colleagues² evaluate the role of a novel molecular imaging technique in assessing extent and progression of ILD in systemic sclerosis. By use of a ⁶⁸Ga-labelled selective inhibitor of prolyl endopeptidase FAP (⁶⁸Ga-FAPI-04) in PET-CT, the authors show that increased uptake of ⁶⁸Ga-FAPI-04 was associated with more extensive ILD in a relatively small number of patients with systemic sclerosis (n=21). Specifically, increased uptake of ⁶⁸Ga-FAPI-04 was observed in patients who had more than 20% radiographic extent of ILD based on visual assessment compared with patients with 20% or less. Similarly, patients with a forced vital capacity (FVC) of less than 70%-predicted had increased uptake of ⁶⁸Ga-FAPI-04 compared with patients with an FVC of 70%-predicted or more. The study also provided some preliminary evidence to suggest that uptake of ⁶⁸Ga-FAPI-04 might be associated with future progression of ILD at 6 months, although validation in larger cohorts with more extensive follow-up is required.

Bergmann and colleagues’ study included a balanced distribution of patients with both limited and diffuse cutaneous systemic sclerosis with a median disease duration of 5 years. The disease duration of the cohort is important to consider in the overall interpretation of the study’s findings. For example, patients with early systemic sclerosis-ILD (≤3 years from the onset of the first non-Raynaud phenomenon symptom attributable to systemic sclerosis) are more likely to have ground glass opacity as the predominant pattern of ILD, in contrast with patients with established systemic sclerosis-ILD, in whom reticulations are more likely to be predominant. For example, in the Scleroderma Lung Study (SLS) I³, which included patients with a mean disease duration of 3·2 years, and SLS II,⁴ which included patients with a mean disease duration of 2·6 years, the quantitative extent of ground glass opacity in the whole lung was more than 20%; by contrast, the quantitative extent of reticulations (fibrosis) was less than 10%.⁵ In Bergmann and colleagues’ study, the extent of ground glass opacity by visual assessment was less than 10% in most patients. As such, it is unknown whether uptake of ⁶⁸Ga-FAPI-04 would correlate with ILD severity in patients with early systemic sclerosis-ILD with a predominantly ground glass pattern of ILD.

Moreover, observational studies have shown that progression of ILD in systemic sclerosis is most likely to occur within the first 5 years of the disease;⁶ therefore, the study of predictive biomarkers of systemic sclerosis-ILD, including studies of ⁶⁸Ga-FAPI-04 PET-CT, should ideally include patients with shorter disease duration, for whom the risk of ILD progression is greatest.

In a small subset of systemic sclerosis-ILD patients (n=5) treated with nintedanib, the authors described changes in ⁶⁸Ga-FAPI-04 uptake that appeared to correlate with changes in lung function. For example, in the one patient who had a loss of lung function during follow-up, ⁶⁸Ga-FAPI-04 uptake was increased compared with baseline; whereas, in the two patients with improved ⁶⁸Ga-FAPI-04 scores on follow-up, lung function also improved. It is unclear why the authors only studied the patients treated with nintedanib for this follow-up analysis, but the findings seem to show that this molecular imaging technique could be sensitive to change.

Without a validation cohort, it is unknown whether the findings are generalisable to other systemic sclerosis-ILD cohorts. Additionally, it is uncertain whether this approach is superior to other existing approaches for measuring the extent and progression of systemic sclerosis-ILD (eg, pulmonary function testing and quantitative imaging analysis⁷), especially when issues, such as cost and radiation exposure, are considered.

However, a major strength of this molecular imaging technique is its ability to discriminate between areas of the lung with active fibrotic remodelling and those without fibrosis. Patients with evidence of active fibrotic remodelling might be more likely to derive benefit from ILD-targeted therapies compared with patients without active fibrotic remodelling. Understanding the dynamic nature of inflammation and fibrosis in the lungs will undoubtedly help in elucidating the optimal treatment windows for initiating and continuing therapy for systemic sclerosis-ILD.

In summary, this proof-of-concept study of ⁶⁸Ga-FAPI-04 PET-CT in systemic sclerosis-ILD showed that quantification of fibroblast activation might be a surrogate marker of the extent of ILD. Larger, multicentre studies that include patients with early systemic sclerosis-ILD are needed to further understand how this novel molecular imaging approach could be used to predict outcomes and personalise treatment strategies for patients with systemic sclerosis-ILD.