Assessment of myocardial fibrosis in patients with systemic sclerosis using [68Ga]Ga-FAPI-04-PET-CT

Abstract

Purpose Myocardial fibrosis (MF) is a factor of poor prognosis in systemic sclerosis (SSc). Direct in-vivo visualization of fibroblast activation as early readout of MF has not been feasible to date. Here, we characterize 68Gallium-labeled-Fibroblast-Activation-Inhibitor-04 ([68Ga]Ga-FAPI-04)-PET-CT as a diagnostic tool in SSc-related MF. Methods In this proof-of-concept trial, six SSc patients with and eight without MF of the EUSTAR cohort Erlangen underwent [68Ga]Ga-FAPI-04-PET-CT and cardiac MRI (cMRI) and clinical and serologic investigations just before baseline and during follow-up between January 2020 and December 2020. Myocardial biopsy was performed as clinically indicated. Results [68Ga]Ga-FAPI-04 tracer uptake was increased in SSc-related MF with higher uptake in SSc patients with arrhythmias, elevated serum-NT-pro-BNP, and increased late gadolinium enhancement (LGE) in cMRI. Histologically, myocardial biopsies from cMRI- and [68Ga]Ga-FAPI-04-positive regions confirmed the accumulation of FAP+ fibroblasts surrounded by collagen deposits. We observed similar but not equal spatial distributions of [68Ga]Ga-FAPI-04 uptake and quantitative cMRI-based techniques. Using sequential [68Ga]Ga-FAPI-04-PET-CTs, we observed dynamic changes of [68Ga]Ga-FAPI-04 uptake associated with changes in the activity of SSc-related MF, while cMRI parameters remained stable after regression of molecular activity and rather indicated tissue damage. Conclusions We present first in-human evidence that [68Ga]Ga-FAPI-04 uptake visualizes fibroblast activation in SSc-related MF and may be a diagnostic option to monitor cardiac fibroblast activity in situ.

Treatment of a patient with severe systemic sclerosis (SSc) using CD19-targeted CAR T cells

“…IgG levels remained above 700 mg/dL in the following 6 months, while ANA reactivity (titre 1:320 at baseline, speckled pattern) was abrogated, and RP11 autoantibodies were no longer detectable (figure 1C) on follow-up of 3 and 6 months. Seroconversion was paralleled by reduced molecular fibroblast activation particularly in the myocardium by 32.6% as determined by 68 Ga-FAPI-04-positron emission tomography–CT (septobasal maximal standard uptake value prior to CAR T cell therapy: 8.6, on follow-up: 5.8)7 (figure 1D). Pulmonary fibrosis remained stable as assessed by CT on follow-up of 3 months and pulmonary function tests (figure 1H) on follow-up of 3 and 6 months.…”

Fibroblast Activation Protein Inhibitor (FAPI)-Based Theranostics—Where We Are at and Where We Are Heading: A Systematic Review

“…Since fibroblast activation can remodel the tissue in fibrosis, inflammation and tissue healing, this may lead to tracer uptake in non-cancerous tissue. It is also worth noting that FAPI tracers have also been studied in non-oncologic diseases, such as IgG4-related disease [ 50 ], cardiac amyloidosis [ 51 , 52 , 53 ], risk of sudden cardiac death [ 54 ], tuberculosis [ 55 ], Crohn’s disease [ 56 ], Erdheim–Chester disease [ 57 ], arthritis and fibrosis. A slight uptake is also seen in the thyroid that may increase in cases of chronic thyroiditis and immune related thyroiditis [ 58 , 59 ].…”

Molecular Imaging of Fibrosis in Benign Diseases: An Overview of the State of the Art

“…FAPI PET/CT was also used to assess activated fibroblasts in IgG4-RD [ 50 ], renal fibrosis [ 51 , 52 , 53 ], pulmonary fibrosis [ 54 , 55 ], liver fibrosis [ 56 ], Crohn’s disease [ 57 ], and systemic sclerosis (SSc) ( Figure 4 B,C) [ 58 , 59 ]. FAPI PET/CT shows promise in furthering disease diagnosis, monitoring disease activity and progression, and evaluating treatment response.…”