FAPi PET/CT for assessment and visualisation of active myositis-related interstitial lung disease: a prospective observational pilot study

Abstract

Background: Interstitial lung disease (ILD) is a common manifestation of idiopathic inflammatory myopathies (IIM) and a substantial contributor to hospitalisation, increased morbidity, and mortality. In-vivo evidence of ongoing tissue remodelling in IIM-ILD is scarce. We aimed to evaluate fibroblast activation in lungs of IIM-patients and control individuals using ⁶⁸Ga-labelled inhibitor of Fibroblast-Activation-Protein (FAPi) based positronic emission tomography and computed tomography imaging (PET/CT).

Methods: In this prospective observational pilot study, consecutive patients with IIM and participants without rheumatic conditions or ILD serving as a control group were recruited at the Medical University of Vienna, Austria, and underwent FAPi PET/CT imaging. Standard-of-care procedures including clinical examination, assessment of severity of dyspnoea, high-resolution computed tomography (HR-CT), and pulmonary function testing (PFT) were performed on all patients with IIM at baseline and for patients with IIM-ILD at follow-up of 12 months. Baseline pulmonary FAPi-uptake was assessed by the maximum (SUVmax) and mean (SUVmean) standardized uptake values (SUV) over the whole lung (wl). SUV was corrected for blood pool background activity and target-to-background ratios (TBR) were calculated. We compared pulmonary FAPi-uptake between patients with IIM-ILD and those without ILD, as well as controls, and correlated baseline FAP-uptake with standard diagnostic tools such as HR-CT and PFT. For predictive implications, we investigated whether patients with IIM and progressive ILD exhibited higher baseline FAPi-uptake compared to those with stable ILD. Metrics are reported as mean with standard deviation (±SD).

Findings: Between November 16, 2021 and October 10, 2022, a total of 32 patients were enrolled in the study. Three participants from the control group were excluded due to cardiopulmonary disease. In individuals with IIM-ILD (n = 14), wlTBR_max and wlTBR_mean were significantly increased as compared with both non-ILD-IIM patients (n = 5) and the control group (n = 16): wlTBR_max: 2.06 ± 1.04 vs. 1.04 ± 0.22 (p = 0.019) and 1.08 ± 0.19 (p = 0.0012) and wlTBR_mean: 0.45 ± 0.19 vs. 0.26 ± 0.06 (p = 0.025) and 0.27 ± 0.07 (p = 0.0024). Similar values were observed in wlTBR_max or wlTBR_mean between non-ILD IIM patients and the control group. Patients with progressive ILD displayed significantly enhanced wlTBR_max and wlTBR_mean values at baseline compared to patients with stable ILD: wlTBR_max: 1.30 ± 0.31 vs. 2.63 ± 1.04 (p = 0.0084) and wlTBR_mean: 0.32 ± 0.08 vs. 0.55 ± 0.19 (p = 0.021). Strong correlations were found between FAPi-uptake and disease extent on HR-CT (wlTBRmax: R = 0.42, p = 0.07; wlTBRmean: R = 0.56, p = 0.013) and severity of respiratory symptoms determined by the New York Heart Association (NYHA) classification tool (wlTBRmax: R = 0.52, p = 0.022; wlTBRmean: R = 0.59, p = 0.0073). Further, pulmonary FAPi-uptake showed inverse correlation with forced vital capacity (FVC) (wlTBRmax: R = -0.56, p = 0.012; wlTBRmean: R = -0.64, p = 0.0033) and diffusing capacity of the lungs for carbon monoxide (DLCO) (wlTBRmax: R = -0.52, p = 0.028; wlTBRmean: R = -0.68, p = 0.0017).

Interpretation: Our study demonstrates higher fibroblast activation in patients with IIM-ILD compared to non-ILD patients and controls. Intensity of pulmonary FAPi accumulation was associated with progression of ILD. Considering that this study was carried out on a small population, FAPi PET/CT may serve as a useful non-invasive tool for risk stratification of lung disease in IIM.

Funding: The Austrian Research Fund.

Keywords: Fibroblast activation; Fibrosis; Idiopathic inflammatory myopathy; Interstitial lung disease.

Fig. 1

Study flow diagram indicating assessment for eligibility for inclusion for pilot study. N = 19 adult patients with idiopathic inflammatory myopathy (IIM) and recently (not older than 4 weeks) available HR-CT and PFT were recruited and included in the study, of whom n = 14 exhibited an interstitial lung disease (ILD). Every IIM patient completed the study. N = 14/14 with IIM-related ILD completed 1-year follow-up as planned. A total of 19 participants (mean age 79 years ± 3.8 [SD]; 14 female) eligible for transcatheter aortic valve implantation (TAVI) were recruited as controls. Three participants from the control group were excluded due to cardiopulmonary disease: n = 2 patients due to aortic stenosis related cardiac decompensation with significantly increased natriuretic peptide levels and signs of pulmonary congestion and oedema; n = 1 patient due to infectious pulmonary disease. Abbreviations: N/n, number; IIM, idiopathic inflammatory myopathy; TAVI, transcatheter aortic valve implantation; RMD, rheumatic and musculoskeletal disease; HR-CT, high-resolution computed tomography; PFT, pulmonary function test.

Fig. 2

Maximum and mean [⁶⁸Ga]⁶⁸Ga-DATA5m.SA.FAPi-derived SUV in the lungs of patients with IIM and controls in relation to blood pool. Mean (SD) whole-lung maximum target-to-background ratio (A); mean value (SD) of whole-lung mean target-to-background ratio in myositis patients with or without interstitial lung disease and control individuals (B). Abbreviations: ILD, interstitial lung disease; wlTBR_max, whole-lung maximum target-to-background ratio; wlTBR_mean, whole-lung mean target-to-background ratio; SD, standard deviation.

Fig. 3

Pulmonary maximum and mean [⁶⁸Ga]⁶⁸Ga-DATA5m.SA.FAPi-derived SUV corrected for the blood pool of patients with IIM and correlations with CT-morphologic extent of total disease and ILD-specific features. Whole-lung maximum and mean target-to-background ratios in myositis patients in relation to semi-quantitative scores of the parenchymal total disease extent (%), extent of ground glass opacities (%), extent of consolidations (%), extent of reticular disease (%) and honeycombing (%) on HR-CT. Abbreviations: wlTBR_max, whole-lung maximum target-to-background ratio; wlTBR_mean, whole-lung mean target-to-background ratio; R, Spearman’s correlation coefficient rho.

Fig. 4

Pulmonary maximum and mean [⁶⁸Ga]⁶⁸Ga-DATA5m.SA.FAPi-PET-derived SUV corrected for the blood pool of patients with IIM in relation to pulmonary function tests (PFTs) at baseline. PFTs (% predicted) showed negative correlations with whole-lung maximum and mean target-to-background ratios. Abbreviations: wlTBR_max, whole-lung maximum target-to-background ratio; wlTBR_mean, whole-lung mean target-to-background ratio; FVC (% predicted), forced vital capacity; DLCO (% predicted), diffusing capacity of the lungs for carbon monoxide; R, Spearman’s correlation coefficient rho.

Fig. 5

Baseline pulmonary FAPi-uptake in relation to non-progressive and progressive ILD. Whole-lung maximum (A) and mean (B) target-to-background ratios of patients with IIM-ILD stratified by non-progressive (n = 6) and progressive (n = 8) ILD within one year. Abbreviations: wlTBR_max, whole-lung maximum target-to-background ratio; wlTBR_mean, whole-lung mean target-to-background ratio.