Large vessel vasculitis (LVV) is a chronic, immune-mediated inflammatory disorder characterized by non-specific granulomatous inflammation, predominantly affecting young Asian women (46). The disease is distinguished by its early onset, protracted course, and elevated mortality rate. As the disease progresses, fibroblasts may significantly contribute to the pathogenesis of vasculitis by influencing the extracellular matrix (ECM), secreting proinflammatory molecules and differentiating into myofibroblasts, which play a role in vascular remodeling (46).

Emerging evidence has highlighted the promising role of FAPI PET/CT in the evaluation of systemic vasculitis, particularly large vessel vasculitis (LVV). In a retrospective study of 30 patients with systemic vasculitis (17 LVV, 10 ANCA-associated vasculitis, 2 Behçet’s disease, 1 polyarteritis nodosa) undergoing dual-tracer imaging, [¹⁸F]FAPI-42 PET/CT demonstrated superior diagnostic performance compared to [¹⁸F]FDG PET/CT. While both modalities showed high positivity rates, [¹⁸F]FAPI detected significantly more lesions (161/168 vs. 145/168) and revealed more extensive vascular involvement in 60% (18/30) of patients. Quantitative analysis showed comparable SUVmax values, but significantly higher TBR for [¹⁸F]FAPI, indicating superior lesion contrast (47). Notably, FAPI uptake shows a moderate correlation with systemic inflammatory markers such as ESR and CRP, supporting its relevance to disease activity (47).

Notably, FAPI imaging provides unique insights into vascular wall remodeling beyond acute inflammation. In a study of LVV patients including both active (n=3) and remitted cases (n=5), FAPI uptake remained visually identifiable in 80% (4/5) of clinically remitted patients despite nearly negative MRI inflammatory scores (48). This persistent uptake suggests ongoing fibroblast activation during the fibrotic remodeling phase. The clinical utility of FAPI PET/CT for therapeutic monitoring is demonstrated by follow-up data from 6 patients showing decreased SUVmax, TBR values, and number of detected lesions paralleling clinical remission (48). Furthermore, in a diagnostically challenging case of active Takayasu arteritis with undetectable blood pressure in bilateral arms and elevated inflammatory markers, [⁶⁸Ga]Ga-FAPI-04 PET/CT demonstrated significant uptake in the arterial walls while initial [¹⁸F]FDG PET/CT showed no abnormal uptake, highlighting FAPI’s potential superior sensitivity in detecting active vascular inflammation (49).

Collectively, these findings suggest that FAPI PET/CT may serve as a sensitive diagnostic tool with high lesion contrast and as a potential biomarker for detecting persistent fibroblast activity during vascular remodeling. This could have implications for disease staging and treatment monitoring in systemic vasculitis, although further validation is required.

Crohn’s disease (CD) represents a chronic, immune-mediated inflammatory bowel disorder characterized by transmural inflammation and progressive intestinal fibrosis (50). Accurate differentiation between inflammatory and fibrotic components is critical for therapeutic decision-making, yet remains challenging with conventional imaging. FAP+ fibroblasts are crucial in the fibrogenesis that leads to excessive extracellular matrix buildup in CD (51).

Animal models reveal distinct dynamics of [¹⁸F]FAPI uptake during fibrogenesis, peaking in early stages (3–6 weeks) and declining later despite persistent fibrosis, reflecting selective visualization of activated rather than quiescent fibroblasts. These findings provide mechanistic context for interpreting clinical FAPI-PET results in CD (52).

[⁶⁸Ga]Ga-FAPI-04 PET/CT demonstrates high sensitivity (93.3%) in identifying endoscopically active lesions, outperforming CT enterography (CTE) (86.7%) (53). The TBR correlates strongly with CTE score and the Simple Endoscopic Score for CD, supporting its role in activity assessment (53). Furthermore, whole-body FAPI uptake scores show significant correlations with fecal calprotectin, CRP, and the CD Activity Index, confirming its utility as a non-invasive biomarker of disease activity (53).

The ability of using [⁶⁸Ga]Ga-FAPI-04 to distinguish fibrotic from inflammatory strictures is well established. Fibrotic bowel segments exhibit significantly higher SUVmax than non-fibrotic segments, with severe fibrosis showing greater uptake than mild-to-moderate fibrosis (54, 55). Importantly, purely inflammatory segments demonstrate lower uptake than those with mixed inflammation and fibrosis (55).

FAPI-PET demonstrates superior diagnostic performance relative to [¹⁸F]FDG PET/CT. A prospective head-to-head study reported higher sensitivity and specificity for FAPI-PET, along with a significantly greater AUC (56). Meta-analytic data further support its advantage, showing that FAPI-PET detects fibrotic lesions with 99% overall sensitivity and approximately twice the diagnostic efficacy of FDG-PET. Pooled analyses reveal a marked SUVmax difference between fibrotic and non-fibrotic segments and a strong correlation with histological fibrosis grading (57).

Current evidence indicates that FAPI-PET may represent a useful functional imaging tool in CD, demonstrating high sensitivity for active inflammation and potential utility in discriminating between fibrotic and inflammatory pathology, with favorable performance compared to FDG-PET in preliminary studies.

Baseline FAPI PET/CT parameters serve as potent predictive biomarkers for therapeutic response. In RA patients, significantly higher baseline levels of PET joint count (PJC_FAPI), total synovitis uptake (TSU_FAPI), and metabolic synovitis volume (MSV_FAPI) were observed in individuals who subsequently achieved an early clinical response at 3-month follow-up compared to non-responders (58). This predictive capacity surpasses that of conventional radiography, which fails to differentiate future responders (10). Following treatment initiation, serial FAPI imaging enables objective monitoring. A significant decrease in synovial and entheseal FAPI uptake has been documented following successful cytokine inhibition (e.g., with TNF or IL-17A antagonists), aligning temporally with clinical resolution (59). This provides a molecular-level confirmation of target engagement and treatment efficacy.

These preliminary observations suggest that baseline FAPI PET parameters may hold predictive value, but the proposed thresholds require validation in larger, independent cohorts. Prospective studies are needed to determine whether treatment adjustments based on FAPI findings translate into improved clinical outcomes.

FAPI PET/CT is instrumental in personalizing treatment by differentiating disease subtypes with distinct therapeutic implications. It effectively distinguishes between inflammatory-dominant lesions (high [¹⁸F]FDG, low FAPI) and fibrosis-dominant lesions (high FAPI). This stratification is clinically critical: the former may optimally respond to immunosuppressive therapy, while the latter, often refractory to anti-inflammatory agents alone, might necessitate adjunctive antifibrotic strategies (30).

In SSc-ILD, FAPI PET/CT provides valuable prognostic information and can inform treatment intensity. Baseline pulmonary FAPI uptake independently predicts future disease progression and correlates with subsequent decline in lung function, regardless of baseline CT findings or pulmonary function test results (34). This capability enables early identification of high-risk patients who may benefit from closer monitoring or timely initiation of antifibrotic therapy. Furthermore, FAPI PET/CT serves as a sensitive tool for monitoring treatment response. Studies have demonstrated that a reduction in pulmonary [⁶⁸Ga]Ga-FAPI-04 uptake during treatment with nintedanib correlates with subsequent improvements in lung function, establishing it as an early imaging biomarker of therapeutic efficacy (34). The prognostic utility of FAPI PET/CT extends to IIM-ILD. Baseline quantitative pulmonary uptake parameters (wlTBRmax, wlTBRmean) are significantly elevated in patients who subsequently experience progressive ILD, as defined by stringent criteria like the INBUILD progression criteria (42). While baseline pulmonary FAPI uptake appears to offer a more responsive measure of fibrotic activity and treatment response, prospective management-impact studies are needed to determine whether FAPI-guided antifibrotic therapy improves long-term outcomes.

Beyond the lungs, FAPI PET/CT also shows promise in assessing cardiac involvement in SSc. In SSc-MF, [⁶⁸Ga]Ga-FAPI-04 uptake correlates moderately with extracellular volume measured by cardiac MRI. Sequential PET imaging has shown a significant 42% ± 8% reduction in tracer uptake in patients with clinical improvement, while conventional cardiac MRI parameters remained stable (35).

FAPI PET/CT shows potential for predicting treatment response in LN. In a study of 20 LN patients, baseline renal [¹⁸F]FAPI SUVmax correlated inversely with eGFR and positively with ESR, while [¹⁸F]FDG uptake showed no significant correlation (45). After six months of therapy, 50% achieved complete renal response (CR), 25% partial response, and 25% no response. CR patients had significantly lower baseline FAPI SUVmax and TBR compared to non-responders. Visual FAPI assessment outperformed FDG in predicting CR, with higher accuracy (85% vs. 70%), specificity (90% vs. 50%), and positive predictive value (89% vs. 64%). Multivariate analysis identified negative baseline FAPI uptake as the sole independent predictor of CR (45).

Renal FAPI uptake correlates with chronicity and treatment non-response, yet prospective trials are required to validate its role in guiding immunosuppression versus antifibrotic therapy. Prediction of long-term renal function preservation remains unestablished.

By precisely distinguishing surgically-indicated fibrotic strictures from inflammation-dominant strictures amenable to medical therapy, FAPI PET/CT directly guides critical treatment decisions in CD management. A recent study suggests that strictures with high SUVmax uptake (≥3.5) are indicative of fibrosis-predominant pathology and warrant consideration for surgical intervention. Conversely, strictures with low SUVmax uptake (<3.5) suggest inflammation-driven pathology, for which intensified medical therapy is the preferred initial approach (54). However, it must be emphasized that the SUVmax threshold of 3.5 was derived specifically from [⁶⁸Ga]Ga-FAPI-04 in single-center cohorts. Its generalizability may be limited by factors such as tracer heterogeneity, protocol variability, and patient selection. Accordingly, its clinical applicability requires multicenter validation and correlation with histopathological findings.

Tracer heterogeneity represents a fundamental and often underappreciated limitation in the current FAPI PET literature. Variability arises at multiple levels: the radionuclide (⁶⁸Ga vs. ¹⁸F), which affects half-life, image resolution, and scan logistics; the chelator or linker scaffold (DOTA, NOTA, quinoline-based), which modulates pharmacokinetics and off-target binding; and the inhibitor variant (FAPI-04, -46, -42), each with distinct biodistribution and target-to-background profiles. As a result, quantitative metrics such as SUVmax, TBR, and TLF are not interchangeable across tracers or protocols. Thresholds established with one tracer cannot be extrapolated to others without dedicated, tracer-specific validation. Table 2 summarizes the key characteristics of commonly used FAPI tracers in AIDs, including radionuclide properties, physiologic uptake, pitfalls, and representative studies.

FAPI PET targets activated fibroblasts, a process central to fibrosis but also present in numerous other conditions including tissue repair, degenerative changes, infection, and malignancy. Thus, FAPI uptake reflects “process specificity” rather than “disease specificity.” Most studies reviewed herein did not systematically address these confounders. To improve diagnostic accuracy, FAPI PET findings must be interpreted in conjunction with clinical context, physical examination, and correlative anatomical imaging (CT/MRI). Histopathological confirmation remains essential in uncertain or suspicious cases.

Despite encouraging preliminary data, establishing FAPI PET/CT as a routine management tool for AIDs still requires bridging several evidence gaps. First, the reproducibility of its quantitative metrics and their correlation with histopathological “gold standards” must be validated in prospective, multicenter cohorts. Second, beyond correlations with surrogate endpoints, there is an urgent need for management impact studies to prospectively assess whether adjusting treatment strategies based on FAPI PET results ultimately improves patient-centered key clinical endpoints (e.g., preservation of organ function, quality of life, progression-free survival). Furthermore, a deeper understanding of the dynamic relationships among FAPI signals, specific fibroblast functional subtypes, the local immune microenvironment, and final clinical outcomes (reversible inflammation versus irreversible fibrosis) is essential. Finally, comprehensive health economic analyses are crucial for clarifying the cost-effectiveness advantages of FAPI PET/CT compared to existing imaging modalities (e.g., ultrasound, MRI) in specific clinical scenarios. This will provide key evidence for its rational clinical integration and resource allocation.