68Ga-FAPI-04 PET-CT for molecular assessment of fibroblast activation and risk evaluation in systemic sclerosis-associated interstitial lung disease: a single-centre, pilot study

Background Interstitial lung disease (ILD) is the most common cause of death in systemic sclerosis. To date, the progression of systemic sclerosis-associated ILD is judged by the accrual of lung damage on CT and pulmonary function tests. However, diagnostic tools to assess disease activity are not available. Here, we tested the hypothesis that quantification of fibroblast activation by PET-CT using a Ga-68-labelled selective inhibitor of prolyl endopeptidase FAP (Ga-68-FAPI-04) would correlate with ILD activity and disease progression in patients with systemic sclerosis-associated ILD. Methods Between Sept 10, 2018, and April 8, 2020, 21 patients with systemic sclerosis-associated ILD confirmed by high-resolution CT (HRCT) within 12 months of inclusion and with onset of systemic sclerosis-associated ILD within 5 years or signs of progressive ILD and 21 controls without ILD were consecutively enrolled. All participants underwent Ga-68-FAPI-04 PET-CT imaging and standard-of-care procedures, including HRCT and pulmonary function tests at baseline. Patients with systemic sclerosis-associated ILD were followed for 6 months with HRCT and pulmonary function tests. We compared baseline Ga-68-FAPI-04 PET-CT uptake with standard diagnostic tools and predictors of ILD progression. The association of Ga-68-FAPI-04 uptake with changes in forced vital capacity was analysed using mixed-effects models. Follow-up Ga-68-FAPI-04 PET-CT scans were obtained in a subset of patients treated with nintedanib (follow-up between 6-10 months) to assess change over time. Findings Ga-68-FAPI-04 accumulated in fibrotic areas of the lungs in patients with systemic sclerosis-associated ILD compared with controls, with a median standardised uptake value (SUV) mean over the whole lung of 0 center dot 80 (IQR 0 center dot 60-2 center dot 10) in the systemic sclerosis-ILD group and 0 center dot 50 (0 center dot 40-0 center dot 50) in the control group (p<0 center dot 0001) and a mean whole lung maximal SUV of 4 center dot 40 (range 3 center dot 05-5 center dot 20) in the systemic sclerosis-ILD group compared with 0 center dot 70 (0 center dot 65-0 center dot 70) in the control group (p<0 center dot 0001). Whole-lung FAPI metabolic active volume (wlFAPI-MAV) and whole-lung total lesion FAPI (wlTL-FAPI) were not measurable in control participants, because no Ga-68-FAPI-04 uptake above background level was observed. In the systemic sclerosis-ILD group the median wlFAPI-MAV was 254 center dot 00 cm(3) (IQR 163 center dot 40-442 center dot 30), and the median wlTL-FAPI was 183 center dot 60 cm(3) (98 center dot 04-960 center dot 70). Ga-68-FAPI-04 uptake was higher in patients with extensive disease, with previous ILD progression, or high EUSTAR activity scores than in those with with limited disease, previously stable ILD, or low EUSTAR activity scores. Increased Ga-68-FAPI-04 uptake at baseline was associated with progression of ILD independently of extent of involvement on HRCT scan and the forced vital capacity at baseline. In consecutive Ga-68-FAPI-04 PET-CTs, changes in Ga-68-FAPI-04 uptake was concordant with the observed response to the fibroblasttargeting antifibrotic drug nintedanib. Interpretation Our study presents the first in-human evidence that fibroblast activation correlates with fibrotic activity and disease progression in the lungs of patients with systemic sclerosis-associated ILD and that Ga-68-FAPI-04 PET-CT might improve risk assessment of systemic sclerosis-associated ILD. Copyright (c) 2021 Elsevier Ltd. All rights reserved.