Multimodality Imaging in Autoimmune Rheumatic Diseases

Immune-mediated systemic inflammatory disorders (IMIDs) are associated with an increased risk of cardiovascular disease (CVD), ranging from atherosclerosis to myocarditis and heart failure.¹ Often, these carry an insidious onset; clinically evident CVD manifestations may not be recognized until late.¹ Multimodality imaging is crucial, and transthoracic echocardiography remains a primary tool because of its widespread availability and affordability; however, there is limited ability to assess for changes at the cellular level.²

Molecular imaging using radiotracers has given health care professionals the ability to conduct noninvasive examinations of cellular-level pathological processes.³ The most commonly used modality, fluorine-18 fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography–computed tomography (PET-CT), facilitates the evaluation of cardiac conditions, including infective endocarditis and sarcoidosis.^4,5 It serves as a proxy marker for visualizing active inflammation in IMIDs through glucose metabolism; however, the noninvasive monitoring of fibrotic remodeling in the heart remains challenging.³

In contrast, cardiac magnetic resonance (CMR) imaging can assess ventricular function, edema, and both pericardial fibrosis and myocardial fibrosis (MF) via late gadolinium enhancement (LGE) in IMIDs.^6,7 LGE in the presence of active T2-weighted edema can suggest inflammation in the correct clinical context in IMIDs. CMR allows for the assessment of focal fibrosis resulting from infarction, myocarditis, or cardiomyopathies.² Additionally, CMR holds the advantage of concurrent myocardial blood flow analysis. Unfortunately, this modality lacks the ability to discern specific molecular alterations, hindering earlier intervention.

Although both ¹⁸F-FDG/PET-CT and CMR have revolutionized clinical understanding of CVD, attention is increasingly focused on the early detection of subclinical injury via the triggering of fibroblast activation (Table 1). Novel radiotracers are under investigation targeting fibroblast activation protein inhibitors (FAPIs) to bridge this gap.³

Fibroblast Activation Protein Inhibitor Positron Emission Tomography

Fibroblasts, which are spindle-shaped connective tissue cells, serve as scaffolding for myocardial structure and facilitation of electrical activity.⁸ In response to myocardial insults, fibroblasts become activated and generate extracellular matrix, including collagen, which plays a crucial role in myocardial healing.⁸ Once activated by inflammation, these fibroblasts express fibroblast activation protein (FAP), also known as seprase or prolyl endopeptidase fibroblast activation protein.⁹ Normally, the expression of FAP in adult tissue is low or absent; however, in the presence of IMIDs, activation may occur.⁹ FAP imaging was initially explored in oncology, as it is highly expressed in the stroma of epithelial tumors.⁹ Various approaches have been developed to effectively target this protease with radiolabeled ligands.⁹ Among these, gallium-68 (⁶⁸Ga)–labeled FAPIs offer the most favorable imaging features with a high detection rate.⁹

Table 1: Mechanistic Insights Into CV Inflammatory Diseases Through Multimodality Imaging

The Potential Role of FAPI in Systemic Inflammatory Diseases

Ubiquitously, IMIDs carry risk of silent cardiac involvement, making it crucial to evaluate for early signs of cardiac involvement in conditions such as rheumatoid arthritis (RA) and systemic scleroderma (SSc).¹ Considering therapies capable of reducing the number of activated fibroblasts in the myocardium could be an effective treatment option to mitigate cardiac fibrosis and improve outcomes.⁸ The first successful applications of ⁶⁸Ga-FAPI/PET-CT in rheumatology originate from studies on SSc-associated interstitial lung disease and immunoglobulin G4–related disease (IgG4-RD).¹⁰

In 2020, researchers conducted an evaluation on a small cohort of patients over the year to examine the effectiveness of FAPI in visualizing fibroblast activation in SSc-related MF.¹¹ FAPI tracer uptake was increased in SSc-related MF among patients with arrhythmias, elevated serum N-terminal pro–B-type natriuretic peptide levels, and increased LGE by CMR.¹¹ Confirmation of FAP-positive fibroblast accumulation surrounded by collagen deposits was obtained through myocardial biopsy.¹¹ These findings provided the first evidence that this radiotracer enables the visualization of activated fibroblasts in SSc-related MF and may serve as a future diagnostic tool for monitoring disease progression and response to therapy.¹¹

IgG4-RD is a fibroinflammatory condition characterized by lymphoplasmacytic infiltration leading to fibrosis and can affect nearly any organ system.¹² In 2021, a prospective cohort study examining 26 patients sought to evaluate organ involvement.^{12 68}Ga-FAPI/PET-CT was found to have higher positive rates than ¹⁸F-FDG/PET-CT in detecting pancreatic, biliary/hepatic, and lacrimal gland involvement.¹² Another area of keen interest is the assessment of cardiac involvement in the setting of RA. FAPI/PET-CT has been used to target fibroblast-like synovioctyes (FLSs), which are centrally involved in the pathogenesis of inflamed joints in patients with RA.^13,14 Whereas studies with ¹⁸F-FDG/PET-CT have evaluated arterial inflammation in patients with RA, the evaluation of FAPI for assessing cardiac disease remains an area open to investigation.¹⁴

However, how broadly this applies to other IMIDs (e.g., systemic lupus erythematosus, which can frequently have myocardial manifestations) requires further evaluation. One distinct utility of FAPI/PET-CT over CMR is the ability to image extracardiovascular manifestations while concurrently affording clues to the extent of disease activity in the heart. Compared with ¹⁸F-FDG/PET-CT, FAPI imaging has the potential for shorter acquisition times and comparable or lower radiation, greatly facilitating longitudinal follow-up for these chronic inflammatory conditions. A summary of FAPI/PET-CT for rheumatological conditions is provided (Table 2).

Table 2: FAPI/PET-CT in Rheumatological Conditions

Conclusion

The progress in molecular imaging techniques, particularly the potential future improvements in FAPI and the impactful use of FDG/PET-CT and CMR, have improved clinical understanding. These advancements are set to revolutionize the management of CVD, especially IMIDs. Researchers have unveiled promising diagnostic and therapeutic avenues, but more investigation is required. These findings underscore the importance of early detection and have started to pave the way for individualized treatment regimens. Ongoing research not only enhances clinical diagnostic capabilities but fuels optimism for the future.

References

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