CXCR4-targeted PET/CT in early systemic sclerosis–associated interstitial lung disease: a prospective proof-of-concept study of in vivo inflammatory activity

Introduction Distinguishing active inflammatory or remodeling-associated processes from irreversible fibrosis in systemic sclerosis remains challenging using conventional imaging modalities. The tracer [ 68 Ga]Pentixafor targets the C-X-C motif chemokine receptor 4 (CXCR4) which is expressed on leukocytes. Uptake of [ 68 Ga]Pentixafor may provide complementary biological information on CXCR4-associated inflammatory and remodeling activity. Methods This prospective cohort study included patients with early SSc (disease duration ≤ 5 years) and preexisting interstitial lung disease. All patients underwent [ 68 Ga]Pentixafor-PET/CT imaging. Normalized [ 68 Ga]Pentixafor uptake was quantified using the target-to-background ratio (TBR). Follow-up data on disease progression was collected. A control group comprised patients with giant cell arteritis. Results Twelve patients with SSc were included. The highest [ 68 Ga]Pentixafor uptake was observed in the hilar and mediastinal lymph nodes, in fibrotic lung regions, and in the left ventricular myocardium. In all three regions, a significantly higher [ 68 Ga]Pentixafor uptake was measured in SSc compared to controls (median TBR of lymph nodes 3.5 [IQR 2.7 – 4.3] vs 1.6 [1.3 – 2.0] p < 0.0001; inferior lung lobes 2.3 [1.6 – 2.8] vs 0.8 [0.7 – 1.0], p < 0.0001; and left ventricle 2.0 [1.4 – 2.4] vs 1.3 [1.1 – 1.5], p = 0.0178). Patients who developed progressive lung disease during follow-up showed a higher [ 68 Ga]Pentixafor uptake compared to non-progressive patients reaching statistical significance in the left ventricle (TBR of progressive vs non-progressive patients: 2.5 (2.1 – 3.3) vs 1.5 (1.3 – 2.1), p = 0.0283) and showing a numerical increase in fibrotic lung regions (2.8 (2.2 – 3.3) vs 1.7 (1.1 – 2.8), p = 0.1535). Conclusion These findings provide proof-of-concept evidence that CXCR4-targeted PET/CT may visualize biologically active inflammatory and/or remodeling processes in early-stage SSc-ILD.