. 2022 Jul 5;13:923869. doi: 10.3389/fimmu.2022.923869

Table 1.

Summary of clinical positron emission tomography studies in patients with systemic sclerosis associated interstitial lung disease.

Study and patient groups	Radiotracer & target	Study design and main findings
Jacquelin et al., 2016 ( 21 ) ◼ SSc-ILD (n = 1) ◼ Other CTD-ILD: IM (n = 2); iNSIP (n = 3); aSS (n = 1); pSS (n = 7); RA (n = 2); aSS + pSS (n = 1); and UCTD (n = 1) Median (range) disease duration of 20 months (1–298)	¹⁸F-FDG GLUT1-4 Glucose metabolism	Retrospective study - All patients with a NSIP pattern on HRCT showed increased pulmonary uptake of ¹⁸F-FDG, the median extent was 19%. - ¹⁸F-FDG was observed in all HRCT identified lesions: consolidations (90%); ground-glass opacities (89%); honeycombing (85%) and reticulations (76%). - Pulmonary ¹⁸F-FDG uptake correlated with pulmonary function improvement under anti-inflammatory treatment, while HRCT fibrosis score and max uptake values did not.
Uehara et al., 2016 ( 22 ) ◼ SSc-ILD (n = 9) ◼ Other CTD-ILD: DM/PM (n = 16); SLE (n = 2); RA (n = 7); MCTD (n = 4); SS (n = 2); AAV (n = 4); and PMR (n = 1) Disease duration unknown	¹⁸F-FDG GLUT1-4 Glucose metabolism	Retrospective study - Visual score and pulmonary ¹⁸F-FDG uptake were higher in the active phase (n=32) compared to the inactive phase (n=37), independent of findings on CT and CTD subtype. Patients were considered at an active phase when immunosuppressive treatment was initiated or intensified. - Seventeen patients that were followed because of active phase showed a decrease in visual score and pulmonary ¹⁸F-FDG uptake after initiation or intensification of treatment. The two patients who died during follow-up showed higher visual uptake compared to the patients that were still alive. - Changes in visual score correlated with Krebs von Lungen-6 and CRP, while pulmonary ¹⁸F-FDG uptake did not.
Bellando et al., 2019 ( 23 ) ◼ SSc (n = 7 of which 3 had ILD) Median disease duration of 5 years	¹⁸F-FDG GLUT1-4 Glucose metabolism	Retrospective study - Pulmonary uptake of ¹⁸F-FDG was higher in patients with higher extent of ILD, measured both in HRCT positive and HRCT negative lesions. - Also, ¹⁸F-FDG uptake was higher in HRCT positive lesions than in HRCT negative lesions in patients with ILD.
Peelen et al., 2020 ( 24 ) ◼ SSc-ILD (n = 5) ◼ Controls: SSc (n = 3), SLE (n = 8) and pSS (n = 4) without ILD Mean disease duration of 5 years	¹⁸F-FDG GLUT1-4 Glucose metabolism	Retrospective study - Pulmonary uptake of ¹⁸F-FDG was higher in dorsobasal regions and as expressed in basal-apical ratios of patients with SSc-ILD when compared to patients without ILD. - Elevated pulmonary uptake of ¹⁸F-FDG coincided with both reticulation and ground-glass lesions on HRCT.
Ledoult et al., 2021 ( 25 ) ◼ SSc (n = 36 of which 22 had ILD) ◼ Controls: Hodgkin Lymphoma (n = 89) Median (range) disease duration of ILD was 2.0 years (0.0 - 8.5)	¹⁸F-FDG GLUT1-4 Glucose metabolism	Retrospective study - Pulmonary uptake of ¹⁸F-FDG was higher in SSc (in general) and SSc-ILD than in controls. No differences were found in regions outside of the lung (skin, lymph nodes, joints, muscles, and esophagus). - SSc patients with progressive ILD showed higher pulmonary uptake of ¹⁸F-FDG than patients with stable disease. - Pulmonary ¹⁸F-FDG uptake correlated with extent of fibrosis and pulmonary function tests.
Branley et al., 2008 ( 26 ) ◼ SSc with fibrosing alveolitis (n = 15) ◼ Controls (n = 7) Mean disease duration of 8 years	¹¹C-[R]-PK11195 PBR Macrophages	Prospective study - A trend of reduced pulmonary uptake of ¹¹C-[R]-PK11195 was seen in patients with SSc with fibrosing alveolitis when compared to controls. - Pulmonary uptake of ¹¹C-[R]-PK11195 was inversely correlated to lung density, which was higher in patients with SSc with fibrosing alveolitis than in controls.
Adams et al., 2019 ( 27 ) ◼ SSc-ILD (n = 1) ◼ Other CTD-ILD: RA (n = 3); aSS (n = 3); cEAA (n = 2); CTD (n = 1) ◼ Controls: RA without ILD (n = 5) Disease duration of 3-6 years	[⁸⁹Zr]Zr-rituximab CD20+ B cells	Prospective study - Pulmonary uptake of [⁸⁹Zr]Zr-rituximab was visual and quantifiable in 4 patients with CTD-ILD after the administration of rituximab. The other patients with CTD-ILD did not show increased pulmonary uptake of this tracer. - In one patient with SSc-ILD uptake of [⁸⁹Zr]Zr-rituximab was mainly seen in lymph nodes, patchy areas in the lung parenchyma and around hilar regions.
Adams et al., 2020 ( 28 ) ◼ SSc-ILD (n = 2) ◼ Other CTD-ILD: cEAA (n = 7); RA (n = 4); aSS (n = 6); CTD (n= 1); DM (n=1) Disease duration of 0-24 years	[⁸⁹Zr]Zr-rituximab CD20+ B cells	Prospective study - Non-responders to Rituximab treatment showed higher splenic uptake of [⁸⁹Zr]Zr-rituximab than responders. - Non-response was defined as a worsening clinical state, while responders improved or stabilized.
Lukey et al., 2020 ( 29 ) ◼ SSc-ILD (n = 1) ◼ Other ILD: RA (n = 1); IPF (n = 7) ◼ Controls (n = 6) Disease duration unknown	¹⁸F-FB-A20FMDV2 Integrin αvβ6	Prospective study - Uptake of ¹⁸F-FB-A20FMDV2 was mainly seen in fibrotic areas, and was higher in patients with ILD than in healthy controls. - ¹⁸F-FB-A20FMDV2 PET/CT repeated after 2 weeks showed reproducible results. - Specifically for SSc-ILD, uptake of the tracer was at lower end of the range, which was probably explained by the fact that only mild fibrotic changes were seen in the lungs of this patient.
Bergmann et al., 2021 ( 30 ) ◼ SSc-ILD (n = 21) ◼ Controls (n = 21) Mean disease duration of 5.5 years	⁶⁸Ga-FAPI-04 FAP-α Activated fibroblasts	Prospective study - Pulmonary uptake of ⁶⁸Ga-FAPI-04 was higher in SSc-ILD than in controls. - In SSc-ILD, pulmonary uptake of ⁶⁸Ga-FAPI-04 was primarily seen in fibrotic lesions and was higher in patients with more extensive ILD and previous ILD progression. Baseline pulmonary uptake of ⁶⁸Ga-FAPI-04 was independently associated with progression of ILD. - In 5 patients with follow-up, changes in pulmonary ⁶⁸Ga-FAPI-04 uptake related to nintedanib response.
Röhrich et al., 2022 ( 31 ) ◼ SSc-ILD (n = 1) ◼ Other ILD: IPF (n = 6); RA (n = 2); cPFE (n = 1); DIP (n = 1); IPAF (n = 2); uILD (n = 1); Sarcoidosis (n = 1) All patients were suspected of lung cancer Disease duration unknown	⁶⁸Ga-FAPI-46 FAP-α Activated fibroblasts	Retrospective study - Patients with ILD showed elevated uptake and high target to background values of ⁶⁸Ga-FAPI-46 at 1 hour after injection in both fibrotic and cancer lesions. - Time activity curves differed between fibrotic and cancer lesions. - After correction for density, uptake of ⁶⁸Ga-FAPI-46 correlated positively with fibrosis index and negatively with ground-glass opacity index.

AAV, ANCA associated vasculitis; aSS, anti-Synthethase Syndrome; cEAA, chronic Extrinsic Allergic Alveolitis; cPFE, combined Pulmonary Fibrosis and Emphysema; CT, Computed Tomography; CTD, Connective Tissue Disease; DIP, Desquamative Interstitial Pneumonia; DM/PM, Dermatomyositis/Polymyositis; FAP-α, Fibroblast Activation Protein Alpha; GLUT1-4, Glucose transporters 1-4; HRCT, High Resolution Computed Tomography; IM, Inflammatory Myositis; iNSIP, idiopathic Non-Specific Interstitial Pneumonia; ILD, interstitial lung disease; uILD, unclassifiable ILD; IPAF, Interstitial pneumonia with autoimmune features; IPF, Idiopathic pulmonary fibrosis; MCTD, Mixed Connective Tissue Disease; PBR, Pheripheral Benzodiazepine receptors; PET, Positron emission tomography; PMR, Polymyalgia Rheumatica; pSS, primary Sjogrens Syndrome; RA, Rheumatoid Arthritis; SLE, Systemic Lupus Erythematosus; SS, Sjogrens Syndrome; SSc, Systemic sclerosis; UCTD, Undifferentiated Connective Tissue Disease.