Interstitial lung disease (ILD) is a common manifestation of systemic sclerosis (SSc) affecting approximately 50% of patients at diagnosis when assessed by high-resolution CT (HRCT).1 ILD is the leading cause of SSc-related mortality and is associated with a threefold increased risk of death in SSc.2 The presence of ILD at SSc diagnosis confers prognostic information.1 Early identification of SSc-ILD may influence the timing of treatment initiation, thus improving outcomes.
68Ga-CBP8 is a positron emission tomography (PET) probe that specifically binds type 1 collagen. In preclinical models, probe uptake strongly correlated with collagen content.3 In patients with idiopathic pulmonary fibrosis (IPF), 68Ga-CBP8 PET detected both increased lung collagen compared with healthy volunteers and decreased lung collagen reflecting treatment effect in a phase II clinical trial.4 5 Performance of 68Ga-CBP8 in non-IPF ILD has not been evaluated. Here, we report the first-in-disease use of 68Ga-CBP8 PET in a small cohort of patients with SSc-ILD.
This study was registered on ClinicalTrials.gov under protocol number NCT03535545. All participants underwent 68Ga-CBP8 PET/MRI. Exclusion criteria included: contraindications to MRI, recent respiratory infection or tobacco use and prior radiation to the thorax. Healthy control data from unmatched subjects were collected as previously described.6 SSc-ILD participant data from a single matched duration (480 s) was used for this analysis. PET data obtained within 60–80 min from injection of 175 MBq (range 113–248) of 68Ga-CBP8 was analysed. Regions of interest (ROIs) were generated by dividing each lung into three axial sections, and further segmenting these into subpleural and central ROIs as previously described.5 Standardised uptake values (SUVs) were obtained from combined left and right lung ROIs. For whole lung analysis, SUVs distributions from all ROIs were combined and then averaged. Group differences were analysed by Mann-Whitney U test (p<0.05, Prism V.10.4). Images from clinical HRCT in subjects with SSc-ILD were visually compared with PET.
Five healthy controls (60% female) and five participants (80% female) with SSc-ILD (n=2) or SSc-ILD overlap syndromes (n=3) (table 1) underwent PET/MRI. Median healthy control age was 32 years (range 22–68) vs 60 years (range 40–72) for the participants with SSc-ILD. Two participants with SSc-ILD had a usual interstitial pneumonia (UIP) pattern on HRCT, and three had a non-specific interstitial pneumonia (NSIP) pattern. All participants with SSc-ILD were receiving immunomodulatory therapy (two on mycophenolate, two on mycophenolate and rituximab and one on tocilizumab and hydroxychloroquine). The participants with a UIP pattern were receiving nintedanib.
Table 1. Characteristics of subjects with SSc-ILD.
| Subject | Age (years) | Sex | SSc subtype | Overlap syndrome | Antibody profile | Treatment | HRCT pattern |
|---|---|---|---|---|---|---|---|
| 1 | 72 | F | Sine | -- | Nucleolar ANA 1:5120 | MMF | NSIP |
| 2 | 68 | F | Diffuse | Sjogren’s | Homogenous ANA 1:640, +SSA/Ro52, +RF | RTX, MMF | NSIP |
| 3 | 56 | M | Limited | Probable antisynthetase | Nucleolar ANA 1:2560, +SSA/Ro52, +RNAPol3 | RTX, MMF, NT | UIP, OP |
| 4 | 60 | F | Limited | Rheumatoid arthritis | Speckled ANA 1:1280, +CCP | Toci, HCQ, NT | UIP |
| 5 | 40 | F | Limited | -- | Speckled ANA 1:1280, +RF | MMF | NSIP, OP |
ANA, antinuclear antibody; CCP, anticitric citrullinated peptide antibody; F, female; HCQ, hydroxychloroquine; HRCT, high-resolution CT; ILD, interstitial lung disease; M, male; MMF, mycophenolate mofetil; NSIP, non-specific interstitial pneumonia; NT, nintedanib; OP, organising pneumonia; RF, rheumatoid factor; RNAPol3, anti-RNA-polymerase 3 antibody; RTX, rituximab; SSA, anti-Sjogren’s syndrome type A antibody; SSc, systemic sclerosis ; Toci, tocilizumab; UIP, usual interstitial pneumonia.
Participants with SSc-ILD had increased whole lung SUVs consistent with an increase in collagen content (median SUV 0.63 (range 0.45–0.81) vs 0.38 (range 0.36–0.43) in healthy controls, p=0.008) (figure 1A). Probe uptake was increased in all ROIs in the participants with SSc-ILD (figure 1B). Additionally, 68Ga-CBP8 uptake coincided qualitatively with regions of reticular or honeycomb change on HRCT (figure 1C,D).
Figure 1. 68Ga-CBP8 PET detects lung collagen in subjects with SSc-ILD. (A,B) Average 68Ga-CBP8 uptake in the whole lung (A) or anatomical regions of interest (B) for subjects with SSc-ILD versus controls. Horizontal line at median for each group. Open triangles: subjects with SSc-ILD subjects on antifibrotic therapy. *p<0.05; **p<0.01. (C,D) Representative HRCT (C) and 68Ga-CBP8 PET (D) performed 1 month later in a subject with SSc-ILD. Red arrows: areas of reticulation and honeycomb change. White arrows: corresponding areas of increased 68Ga-CBP8 lung uptake. Scale bar shows SUVs. ILD, interstitial lung disease; PET, positron emission tomography; SSc, systemic sclerosis; SUV, standardised uptake values.
Measuring lung collagen may have important implications for patients with SSc-ILD. We demonstrate that 68Ga-CBP8 PET can detect fibrotic changes in a cohort of participants with SSc-ILD that included NSIP and UIP radiological patterns. Despite the heterogeneity of the SSc-ILD group, our findings suggest that collagen deposition is an important feature of all types of SSc-ILD. Although age did not correlate with 68Ga-CBP8 uptake within either the control group or SSc-ILD group (data not shown), our sample size is small, and it is possible that the age difference between groups may have confounded the degree of difference in CBP8 lung uptake between groups. Additionally, three of the participants with SSc-ILD had overlap syndromes (table 1). To what extent this influenced our results is unknown. It is mechanistically plausible that variations in use of immunomodulatory and antifibrotic therapy within the SSc group could affect our measured SUVs. Due to our small numbers, we are unable to assess for correlations with 68Ga-CBP8 uptake and disease severity or association with subsequent change in pulmonary function. Further research is needed to determine if the degree of 68Ga-CBP8 uptake predicts the development of progressive pulmonary fibrosis. This would also yield insight into the ability of 68Ga-CBP8 to serve as a marker of disease activity, thereby adding value to information provided from conventional HRCT for SSc-ILD and other autoimmune-related ILDs.
Footnotes
Funding: This study was funded by the National Scleroderma Foundation and the National Institutes of Health (R01HL131907, R01HL171240 and T32HL116275). Development of the imaging methodology and the radiochemistry equipment used was supported by awards from the National Institutes of Health (R01HL153606, R01HL171240, K25HL148837, K23HL150331, S10OD028499 and S10OD032138).
Patient consent for publication: Not applicable.
Ethics approval: This study was approved by the Massachusetts General Brigham Institutional Review Board under protocol number 2017P002718. All participants provided informed consent before enrolment.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data availability free text: The data that support the findings of this study are available from the corresponding author (MBA) on reasonable request.
References
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