Complementary Roles of 68Ga-FAPI and 18F-FDG PET/CT in Evaluating IgG4-Related Disease: A Systematic Review and Pooled Analysis

Complementary Roles of 68Ga-FAPI and 18F-FDG PET/CT in Evaluating IgG4-Related Disease: A Systematic Review and Pooled Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Complementary Roles of 68Ga-FAPI and 18F-FDG PET/CT in Evaluating IgG4-Related Disease: A Systematic Review and Pooled Analysis Xue CAI, Qingfan HAO, Jian ZHANG This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8932863/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract 1.1. Background IgG4-related disease (IgG4-RD) lacks standardized imaging criteria. This study systematically reviewed head-to-head comparisons of 68 Ga-FAPI and 18 F-FDG PET/CT to clarify their complementary roles in diagnosing and staging IgG4-RD. 1.2. Main body Three high-quality studies (n = 90) were pooled. 68 Ga-FAPI showed significantly higher SUVmax and target-to-background ratios (TBR) in parenchymal organs (pancreas, salivary glands) vs 18 F-FDG ( P < 0.001), offering superior lesion contrast. While 18 F-FDG detected more lymph node activity, 68 Ga-FAPI identified 136 vs 78 total lesions, improving systemic burden assessment. Pathology correlated FAPI with fibrosis and FDG with inflammation, defining a "flip-flop" pattern. A FAPI/FDG ratio ≥ 1.5 predicted relapse risk. 1.3. Conclusion 68 Ga-FAPI excels in parenchymal organ involvement, while FDG highlights inflammatory lymphadenopathy. Combining both tracers enables multimodal evaluation of fibroinflammatory activity, guiding personalized management and prognostication in IgG4-RD. IgG4-related disease 68Ga-FAPI 18F-FDG PET/CT head-to-head comparison fibrosis PET index Figures Figure 1 Figure 2 Figure 3 2. Background IgG4-related disease (IgG4-RD) is a rare immune-mediated fibroinflammatory condition capable of involving multiple organs, characterized by lymphoplasmacytic infiltration rich in IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis [1] .The diagnosis of IgG4-RD poses challenges and often requires a comprehensive assessment combining serology, imaging, and pathology [2] .Imaging techniques are crucial for identifying involved organs, guiding biopsies, and monitoring treatment response [3] .Although 18 F-FDG PET/CT, a commonly used molecular imaging method, can visualize metabolically active lesions throughout the body, it is associated with issues of false negatives and false positives in IgG4-RD [4] . Recently, 68 Ga-FAPI PET/CT, a novel imaging technique targeting fibroblast activation protein (FAP), has demonstrated potential in fibrotic diseases [5] . The pathological essence of IgG4-RD is immune-inflammation-driven fibrosis, wherein fibroblast activation protein (FAP) is highly expressed in activated fibroblasts and serves as a key marker of fibrotic activity. 68 Ga-labeled FAPI inhibitors ( 68 Ga-FAPI), by specifically targeting FAP, allow for the direct visualization of active fibrotic regions, overcoming the metabolism-dependent limitations of FDG [6] , and are characterized by high specific binding to FAP, low background noise, rapid blood clearance, and favorable biosafety [7] . Studies have shown that FAP is significantly upregulated in fibroblasts within IgG4-RD involved organs, particularly in the pancreas, biliary tract, and salivary glands [8] . Furthermore, FAPI can distinguish active fibrosis from old scars, as the latter do not uptake FAPI due to fibroblast inactivation [9] .Theoretically, FAPI PET/CT can also assess the degree of fibrosis by quantifying FAP expression levels, providing an objective basis for disease staging [10] . Compared with FDG, FAPI exhibits a higher target-to-background ratio (TBR), showing distinct advantages especially in organs with high physiological uptake such as the liver and pancreas [11] . This study aims to provide evidence-based medical evidence for clinical selection by directly comparing (head-to-head) the lesion detection rates, uptake intensity, and image contrast of the two tracers in IgG4-RD through a systematic review and meta-analysis. 3. Main Text 3.1. Materials and Methods 3.1.1. Study Protocol and Registration This systematic review and pooled analysis was conducted in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement.The study protocol was designed to meet high methodological standards for diagnostic accuracy assessment. 3.1.2. Search Strategy and Data Sources We performed a comprehensive systematic literature search in three major electronic databases: PubMed, Embase, and Web of Science.The search spanned from the inception of each database to February 1, 2026. To ensure a broad and comprehensive retrieval of relevant studies, the search strategy combined Medical Subject Headings (MeSH) and free-text keywords, including but not limited to "IgG4-Related Disease," "Fibroblast Activation Protein Inhibitor," "FAPI," "FDG," and "PET/CT".The search was restricted to articles published in English.We refined the search results using Boolean operators (AND, OR). 3.1.3. Inclusion Criteria and Study Selection Studies meeting the following criteria were included in this review: (1) comparative studies or clinical trials involving patients with histopathologically or clinically confirmed IgG4-RD; (2) subjects underwent a head-to-head comparison of 68 Ga-FAPI and 18 F-FDG PET/CT; and (3) sufficient quantitative data (e.g., SUVmax, lesion detection rate) were reported to allow for pooled analysis.Case reports, reviews, editorials, conference abstracts, and non-comparative studies were excluded. 3.1.4. Data Extraction and Quality Assessment Literature screening and data extraction were independently performed by two investigators (Q.F.H. and X.C. ).Any discrepancies regarding study inclusion or data extraction were resolved through consensus via group discussion or, if necessary, consultation with a third senior reviewer.The methodological quality and potential risk of bias of the included studies were rigorously assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2), the recommended standard tool for diagnostic accuracy evaluation. 3.1.5. Statistical Analysis All statistical analyses and graph plotting were performed using GraphPad Prism software (Version 9.0, GraphPad Software, San Diego, CA, USA). Continuous variables (such as maximum standardized uptake value [SUVmax] and target-to-background ratio [TBR]) were expressed as mean ± standard deviation (SD).Differences in quantitative uptake values between 68 Ga-FAPI and 18 F-FDG were evaluated using the paired Student's t-test or Wilcoxon matched-pairs signed-rank test, depending on the normality of the data distribution.In the assessment of lesion detection capability, categorical data were expressed as frequencies (n) and percentages (%). Differences in lesion detection rates between the two tracers were analyzed using the Chi-square test or Fisher's exact test. A P -value of less than 0.05 was considered statistically significant (* P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001). 3.2. Results 3.2.1. Literature Search Results The initial search identified a total of 169 relevant articles across the three major databases (PubMed, Embase, and Web of Science).After automatic de-duplication using reference management software supplemented by manual verification, 70 duplicate records were removed, leaving 99 articles for the preliminary screening phase.Following a rigorous screening of titles and abstracts, the majority of articles unrelated to the study topic, reviews, case reports, and animal studies were excluded, leaving 17 articles for full-text assessment.Through careful reading and strict review of the full texts, studies with non-head-to-head comparison designs, lack of key quantitative data, or overlapping patient cohorts were further excluded. Finally, a total of 3 high-quality studies meeting all inclusion and exclusion criteria (Luo et al., Liu et al., Schmidkonz et al.) were included in this systematic review and pooled analysis.The detailed literature screening and inclusion process is shown in Fig. 1.( Fig. 1 ) Figure 1 PRISMA 2020 flow diagram illustrating the literature search and study selection process 3.2.2. Methodological Quality Assessment The risk of bias and applicability of the 3 included studies (Luo et al., Liu et al., Schmidkonz et al.) were assessed using the QUADAS-2 tool, with results indicating a high overall methodological quality of the included studies (Fig. 2 ). Figure 2 Summary of the methodological quality of the included studies according to the QUADAS-2 tool In the "Patient Selection" domain, all studies explicitly described inclusion criteria and avoided case-control design bias, thus being rated as low risk.In the "Index Test" and "Reference Standard" domains, as all patients underwent head-to-head comparisons of 68 Ga-FAPI and 18 F-FDG PET/CT within a short interval, and diagnostic results were referenced against histopathology or clinical follow-up with proper blinding, no significant measurement bias was detected.Additionally, no attrition or inappropriate exclusion was observed in any study regarding "Flow and Timing". In summary, all included studies were evaluated as "Low Risk" in terms of bias risk and clinical applicability, with no "High Risk" or "Unclear" items found, indicating a robust and reliable evidentiary basis for this systematic review. 3.2.3. Study Characteristics and Baseline Data The 3 studies finally included in this systematic review and pooled analysis (Luo et al., Liu et al., Schmidkonz et al.) comprised a total of 90 patients with histopathologically or clinically confirmed IgG4-related disease (IgG4-RD).All patients completed head-to-head comparisons of 68 Ga-FAPI and 18 F-FDG PET/CT within a short time interval.Among these 3 studies, one was a prospective cohort design (Luo et al., 2020), and two were retrospective comparative studies (Liu et al., 2025; Schmidkonz et al., 2020).The study locations were distributed in China (2 studies) and Germany (1 study), representing data from Asian and European populations, respectively.The median age of patients ranged from 58 to 61 years, with a higher proportion of male patients than females (male:female ratio approximately 2:1), consistent with the epidemiological characteristics of IgG4-RD.The study by Liu et al. further subdivided patients into proliferative and fibrotic subgroups. Detailed baseline characteristics of the included studies are presented in Table 1 .(Table 1 ) Table 1 Baseline information of comparative studies enrolled in the meta-analysis References Country Year Design Patients Imaging examinations Age No. of patients Luo et al. China 2020 Prospective cohort study Histopathologically or clinically diagnosed IgG4-RD 68 Ga-FAPI-04 PET/CT 18 F-FDG PET/CT Median age 61 (range 35–78) 26 (19 m; 7 f) Liu et al. China 2025 Comparative study Newly diagnosed IgG4-RD (Proliferative & Fibrotic subtypes) 68 Ga-FAPI-04 PET/CT 18 F-FDG PET/CT Median age 58 (range 31–82) 37 (25 m; 12 f) Schmidkonz et al. Germany 2020 Comparative study IgG4-RD patients with histopathological confirmation 68 Ga-FAPI-04 PET/CT 18 F-FDG PET/CT Median age 60 (range 40–80) 27 (18 m; 9 f) Table 1 Baseline information of comparative studies enrolled in the meta-analysis 3.2.4. Data Pooled Analysis Although this systematic review included 3 studies with 90 patients, due to differences in data reporting formats, only 2 studies (Luo et al. and Liu et al., totaling 63 patients) provided compatible Mean ± SD data and were thus included in the quantitative pooled analysis (Meta-analysis) for SUVmax.The study by Schmidkonz et al. (n = 27), which reported only medians and ranges, could not be directly statistically pooled and was therefore included only for qualitative description, excluded from quantitative graphical analysis.Given the small number of included studies, we employed a sample-size weighted mean to calculate the pooled SUVmax and TBR.( Fig .3 ) Fig .3 Head-to-head comparison of quantitative parameters.Panel A shows that 68 Ga-FAPI has significantly higher SUVmax values than 18 F-FDG in lymph nodes, salivary glands, and the pancreas ( P < 0.0001), indicating stronger lesion uptake. Panel B demonstrates that 68 Ga-FAPI yields significantly higher target-to-background ratios (TBR) in the pancreas and salivary glands ( P < 0.0001), suggesting superior lesion-to-background contrast. Panel C reveals that 68 Ga-FAPI detects significantly more lesions than 18 F-FDG (P < 0.0001), highlighting its advantage in lesion detection rates. 3.2.5. Semi-quantitative Uptake Intensity Pooled analysis based on the two mergeable head-to-head comparative studies (Luo et al. and Liu et al., totaling 63 patients) revealed significant differences in the uptake patterns of 68 Ga-FAPI and 18 F-FDG across different involved organs (Fig. 3-A).In involved pancreatic parenchyma, the mean SUVmax of 68 Ga-FAPI was significantly higher than that of 18 F-FDG ( P < 0.001), indicating that FAPI possesses higher activity in reflecting pancreatic fibroinflammation.Similarly, in submandibular/parotid gland lesions, 68 Ga-FAPI also exhibited significantly higher radiotracer uptake ( P < 0.001).However, an opposite trend was observed in lymph node lesions: the uptake value of 18 F-FDG was significantly higher than that of 68 Ga-FAPI ( P < 0.001).This organ-specific "flip-flop phenomenon" suggests that the two tracers may reflect the metabolic characteristics of different pathological components (inflammation vs. fibrosis) of IgG4-RD. 3.2.6. Lesion Detection Capability In the assessment of lesion detection capability, 68 Ga-FAPI demonstrated sensitivity superior to that of 18 F-FDG (Fig. 3-B).Based on data analysis from a representative study (Luo et al.), 68 Ga-FAPI PET/CT detected a total of 136 IgG4-RD-related lesions, whereas concurrent 18 F-FDG PET/CT detected only 78 lesions.The overall lesion detection rate of 68 Ga-FAPI was significantly higher than that of 18 F-FDG ( P < 0.001). 68 Ga-FAPI was able to identify more involved organs missed by 18 F-FDG, with particularly evident detection advantages in pancreatic, biliary, and certain retroperitoneal fibrosis lesions, thereby more accurately assessing the pan-scan extent of the disease. 3.2.7. Image Contrast and Target-to-Background Ratio (TBR) To evaluate image quality and lesion visualization, we compared the target-to-background ratio (TBR) of the two tracers (Fig. 3-C).Benefiting from extremely low abdominal background uptake, 68 Ga-FAPI demonstrated superior image contrast in parenchymal organs. In pancreatic lesions, the mean TBR of 68 Ga-FAPI reached 18 .02 ± 13.91, which was more than 5 times that of 18 F-FDG (3.44 ± 2.05), a difference of high statistical significance ( P < 0.001).Similarly, in salivary gland lesions, the TBR of 68 Ga-FAPI (9.92 ± 5.61) was significantly higher than that of 18 F-FDG (3.12 ± 1.51, P < 0.001).These results indicate that 68 Ga-FAPI provides a higher signal-to-noise ratio, rendering lesion boundaries clearer and facilitating the identification of small lesions. 3.2.8. Heterogeneity in Treatment Response Monitoring Based on the analysis of longitudinal follow-up data from the study by Schmidkonz et al., the two tracers exhibited significant biological differences in assessing treatment response.Following anti-inflammatory therapy (e.g., rituximab or glucocorticoids), the vast majority of lesions with high baseline uptake showed a significant reduction or even disappearance of metabolic activity on 18 F-FDG PET/CT, suggesting effective control of inflammatory infiltration.However, within the same group of lesions, 68 Ga-FAPI radiotracer uptake showed varying degrees of persistence after treatment; in some involved organs (particularly the pancreas and retroperitoneal regions), the FAPI signal remained at a relatively high level despite some attenuation.This phenomenon of "FDG-negative but FAPI-persistent" was corroborated at the immunofluorescence level, indicating that while treatment successfully cleared or suppressed lymphocytes (CD45+), it failed to fully reverse activated fibroblasts (FAP+) and the associated fibrotic remodeling process. 3.3. Discussion 3.3.1. Pathophysiological Mechanisms of FAPI Advantages The core mechanism of action of fibroblast activation protein inhibitors (FAPI) relies on their high specific binding to fibroblast activation protein (FAP).FAP is highly expressed on the surface of activated fibroblasts, being significantly upregulated particularly in cancer-associated fibroblasts (CAFs) within the tumor microenvironment, wound healing, and inflammatory fibrosis processes [ 12 ] . FAPI tracers achieve precise targeting of activated fibroblasts by covalently binding to the catalytic site of FAP [ 13 ] . A systematic review on Crohn's disease by Abdlkadir, AS et al. [ 14 ] showed that FAPI PET achieved a detection rate of 99% for intestinal wall fibrosis, with sensitivity and specificity of 92% and 93% respectively, significantly superior to the 76% and 81% of [ 18 F]FDG.This mechanism enables FAPI PET to directly visualize active fibrotic regions, reflecting the matrix remodeling process more specifically than metabolism-dependent 18 F-FDG [ 15 ] .IgG4-related disease (IgG4-RD) is a unique fibroinflammatory condition whose disease progression involves the synergistic action of immune dysregulation and fibrosis [ 16 ] .As the disease progresses, fibrosis gradually replaces inflammation as the dominant pathological change, leading to sclerosing organ enlargement and dysfunction.This dynamic evolution explains the utility of FAPI in IgG4-RD: it can capture inflammation-related fibrosis in the early stages and assess fibrotic burden in the late stages to guide corticosteroid therapy [ 9 ] . Research by Mori, Y et al. [ 17 ] on IgG4-related disease concluded that FAPI uptake correlates significantly with histological fibrosis grading (r = 0.54–0.57, P < 0.01) and can predict treatment response.In cases of IgG4-related pancreatitis, FAPI PET clearly demonstrated diffuse high uptake in the pancreas (SUVmax = 8.8), whereas 18 F-FDG showed mild uptake (SUVmax = 2.5), with pathology ultimately confirming fibrosis-dominant lesions [ 18 ] . Interference from high-uptake organs is a critical factor affecting diagnostic accuracy, and the low-background characteristic of FAPI effectively addresses this challenge.In conventional 18 F-FDG PET, high physiological uptake in the brain (SUVmax = 11.01), liver (SUVmean = 2.77), and urinary system often obscures adjacent lesions, such as brain metastases or small intrahepatic lesions [ 19 ] .In contrast, FAPI uptake in normal brain tissue is extremely low (SUVmax = 0.32), increasing the detection rate of intracranial metastases to 87.9%, far exceeding the 46.3% of 18 F-FDG [ 20 ] .In the liver, the background uptake of FAPI (SUVmean = 1.69) is significantly lower than that of 18 F-FDG, increasing the target-to-background ratio (TBR) of intrahepatic lesions from 2.8 to 5.1 and boosting detection sensitivity for small lesions (≤ 1cm) by 30% [ 21 ] . In bladder cancer, [ 18 F]FDG causes high radioactivity within the bladder due to urinary excretion, making tumor indistinguishable from urine, whereas FAPI is excreted via the kidneys but does not concentrate in the bladder, achieving a detection sensitivity of 100% for primary tumors [ 22 ] .Additionally, FAPI uptake in salivary glands (SUVmean = 2.57) and the gastrointestinal tract (e.g., colon SUVmean = 1.8) is lower than that of [ 18 F]FDG, reducing false negatives in the diagnosis of head and neck and abdominal tumors [ 12 ] . The advantage of FAPI in abdominal lesions stems primarily from its low physiological uptake and rapid clearance characteristics, which significantly improve lesion detection rates. In pancreatic cancer assessment, FAPI resolves the issue of lesion blurring caused by physiological pancreatic uptake and adjacent intestinal concentration seen with [ 18 F]FDG.A meta-analysis showed that FAPI sensitivity for detecting primary pancreatic lesions reached 100%, higher than the 88.9% of 18 F-FDG (MD = 7.51, P < 0.001) [ 23 ] .In liver metastases, the low hepatic background of FAPI (SUVmean = 1.5) resulted in a TBR of 4.4 for colorectal liver metastases, significantly higher than the 1.8 of [ 18 F]FDG ( P = 0.042) [ 24 ] .The low-background characteristic of FAPI comprehensively improves diagnostic accuracy by enhancing lesion contrast and reducing false positives. 3.3.2. Discussion on the "Flip-flop Phenomenon As immune organs, the physiological structure of lymph nodes and the dynamic changes in cellular composition (such as lymphocytes, macrophages, CAFs) under pathological conditions directly affect the distribution and signal characteristics of FDG and FAPI, resulting in the "flip-flop phenomenon"—where the uptake patterns of FDG and FAPI in benign versus malignant lymph nodes may be opposite or complementary [ 25 ] .Anatomically, lymph nodes consist of a capsule and internal parenchyma.The capsule is dense connective tissue that extends into the parenchyma to form trabeculae, constituting the scaffold of the lymph node.The parenchyma is divided into the peripheral cortex and the central medulla [ 26 ] .The stromal cell network of lymph nodes, particularly fibroblastic reticular cells (FRCs), constitutes a crucial 3D scaffold. As key stromal cells maintaining lymph node structure, FRCs typically exhibit low metabolic activity and FAP expression levels under steady-state conditions.Consequently, normal non-enlarged lymph nodes usually show mild or no 18 F-FDG uptake (SUVmax typically below 2.5), while FAPI uptake is even lower or close to background levels [ 27 ] .When lymph nodes encounter antigenic stimulation (e.g., infection, tumor antigens), reactive hyperplastic lymph nodes show significantly increased 18 F-FDG uptake, often exhibiting a diffuse, symmetrical distribution, which is a major source of false positives [ 28 ] .Studies show that in chronic inflammation or autoimmune diseases (e.g., rheumatoid arthritis, sarcoidosis, systemic sclerosis), involved lymph nodes can present with diffuse high FDG uptake, forming the basis for FDG positivity in the so-called "flip-flop phenomenon" [ 29 ] .In metastatic lymph nodes, in addition to the stromal reaction induced by tumor cells themselves (inducing host fibroblast conversion to CAFs), CAFs infiltrating the metastatic foci also abundantly express FAP.FAP expression levels become key to distinguishing benign from malignant lymph nodes: reactive hyperplasia (acute inflammation) typically has low FAP expression, while metastatic lymph nodes (especially epithelial tumor metastases) have high FAP expression due to CAF richness [ 30 ] . Therefore, the "flip-flop phenomenon" in lymph node assessment implies that under specific pathological conditions, 18 F-FDG PET/CT and FAPI PET/CT may present opposite or complementary signal patterns for determining the benign or malignant nature of the same lymph node. The application of FDG-PET in IgG4-RD has been widely confirmed for its value in assessing disease activity and organ involvement, particularly in lymph node involvement. Research indicates that lymph nodes in IgG4-RD patients often exhibit high FDG uptake, with standardized uptake values (SUVmax) significantly higher than normal tissue, averaging between 4.0 and 7.0, reflecting a state of local metabolic activity [ 31 ] .This high uptake characteristic correlates with the inflammatory nature of the disease; as a glucose analog, FDG accumulates in activated immune cells (such as lymphocytes and plasma cells), highlighting the lymphoplasmacytic infiltration characteristic of IgG4-RD lymph nodes [ 32 ] .Clinical case studies have further confirmed the practical application value of FDG-PET regarding the high uptake characteristics in IgG4-RD lymph nodes.A retrospective multicenter study including 21 IgG4-RD patients found that all patients showed abnormal lymph node FDG uptake at diagnosis or relapse, especially in mediastinal and hilar regions, and FDG-PET sensitivity (> 90%) exceeded that of conventional imaging like CT or MRI, with significant advantages in detecting small or asymptomatic lesions [ 4 ] .In a case study by Taniguchi et al. [ 33 ] , a 74-year-old patient showed increased FDG uptake in the spleen and lymph nodes (SUVmax > 6) on FDG-PET, which was confirmed by biopsy as IgG4-RD-related splenopathy and lymphadenitis.In IgG4-RD, FAPI-PET is used to assess the degree of fibrosis because the disease is characterized by storiform fibrosis and theoretically should show high uptake; however, in practice, it presents a phenomenon of low lymph node uptake.In terms of technical parameters, the SUVmax of FAPI-PET in lymph nodes is lower than that of FDG, reflecting the heterogeneity of FAP expression [ 34 ] .Lymph nodes are dominated by lymphoid follicular hyperplasia rather than significant storiform fibrosis, resulting in an insufficient number of FAP-positive fibroblasts. A prospective study by Luo et al. [ 8 ] clearly indicated that while involved lymph nodes showed high FDG uptake, there was no FAPI accumulation, supporting the hypothesis of a low degree of fibrosis.Secondly, disease subtype differences affect FAP expression: IgG4-RD can be classified into proliferative and fibrotic types, with the proliferative type dominated by inflammatory cell infiltration and the fibrotic type by fibrosis; research shows that FAPI uptake in the fibrotic subtype is significantly lower than in the proliferative type (SUVmax 10.93 vs. 17.67, P = 0.005), and lymph nodes may more commonly belong to the proliferative or mixed type, leading to attenuated FAPI signals [ 35 ] .Furthermore, microenvironmental factors such as cytokine profiles may inhibit fibroblast activation.Early lymph node disease is dominated by inflammation, and FAPI uptake may enhance after fibrosis progression in later stages, but most studies focus on active-phase cases, underestimating late-stage changes [ 36 ] . This hypothesis regarding the "separation of inflammation and fibrosis" was directly validated pathologically in the study by Schmidkonz et al. [ 36 ] .The study confirmed via immunofluorescence analysis of IgG4-RD patient tissues that 18 F-FDG uptake is highly correlated with the infiltration density of CD45 + lymphoplasmacytes (representing inflammatory activity), whereas 68 Ga-FAPI uptake specifically corresponds to the abundance of FAP+/Vimentin+ activated fibroblasts (representing fibrotic burden).More importantly, this difference in pathological mechanisms directly leads to the "divergent" performance of the two in treatment monitoring.After anti-inflammatory therapy (e.g., rituximab), although inflammation-dominant lesions showed a significant decrease in FDG uptake, FAPI signals persisted in some lesions, revealing residual fibrotic activity after pure anti-inflammatory treatment.This finding not only explains the aforementioned imaging discrepancies but also establishes a biological foundation for the application of FAPI in clinical efficacy monitoring. 3.3.3. Clinical Translational Significance of FAPI PET in IgG4-RD The emergence of FAPI PET brings a revolutionary tool for the precise diagnosis and comprehensive assessment of IgG4-RD.By targeting activated fibroblasts—the key effector cells in the fibrosis process—it overcomes the inherent limitations of traditional imaging modalities, significantly improving the accuracy of disease detection and staging. Although 18 F-FDG PET/CT is commonly used to assess IgG4-RD, limited by its dependence on glucose metabolism, it often suffers from insufficient lesion detection sensitivity and contrast due to high physiological uptake in organs masking lesions or overlapping uptake between lesions and inflammation/tumors [ 37 ] .FAPI PET fundamentally alters this predicament. Its target, FAP, is highly expressed in activated fibroblasts [ 12 ] . This characteristic endows FAPI PET with extremely low physiological background signals system-wide, thereby achieving superior target-to-background contrast.Studies indicate that FAPI PET can discover additional involved organs that FDG PET/CT or other conventional imaging modalities failed to detect.A typical case is the detection of lacrimal gland involvement by FAPI PET that was not shown by FDG, which directly influenced the patient's clinical staging and treatment decision [ 38 ] .Furthermore, a study based on [ 18 F]AlF-NOTA-FAPI-04 PET/CT found that in up to 50% of IgG4-RD patients, the number of involved organs detected by PET/CT exceeded the sum of those found by physical examination, ultrasound, and CT [ 10 ] .Moreover, FAPI PET helps distinguish disease subtypes, preventing misjudgment of disease activity.The study by Liu et al. [ 35 ] classified IgG4-RD into two subtypes: proliferative and fibrotic.The proliferative type is characterized primarily by inflammatory cell infiltration, while the fibrotic type is characterized by significant fibrosis.These two subtypes differ distinctly in their response to treatment and prognosis.FDG PET uptake may be similar in these two subtypes, making them difficult to distinguish.However, FAPI PET can effectively differentiate between the two.It was found that FAPI uptake in lesions of proliferative subtype patients (SUVmax: 17.67 ± 7.46) was significantly higher than in the fibrotic subtype (SUVmax: 10.93 ± 2.22, P = 0.005), and their target-to-background ratio (TBR) was also higher (15.49 ± 8.23 vs. 9.25 ± 3.00, P = 0.015) [ 35 ] .More importantly, the "PET index" (FAPI SUVmean / FDG SUVmean) proposed by the researchers was significantly higher in the proliferative subtype compared to the fibrotic type (1.46 ± 0.41 vs. 1.14 ± 0.39, P = 0.039) [ 35 ] .This index can quantify the weight of fibroinflammatory activity, directly reflecting disease activity. For fibrotic patients, relying solely on FDG PET might lead to a misjudgment of stable disease due to low metabolism, while active fibrosis is actually progressing silently. Changes in FAPI PET uptake before and after treatment can serve as direct imaging biomarkers for fibrosis reversal or progression.A preclinical study monitoring pulmonary fibrosis treatment using FAPI PET provided strong evidence for this concept.In that study, untreated mouse models of pulmonary fibrosis showed [ 68 Ga]FAPI uptake peaking at 21 days, whereas after treatment with the anti-fibrotic drug pirfenidone, FAPI uptake in the mouse lungs significantly decreased, consistent with a reduction in histologically measured fibrotic area [ 39 ] .This model clearly demonstrates that FAPI PET can track the response of fibrosis to treatment in real-time and with accuracy.Applying this principle to IgG4-RD, we can perform periodic FAPI PET examinations during treatment to determine the effectiveness of anti-fibrotic therapy by quantitatively analyzing changes in lesion SUVmax, TBR, or total load (e.g., TL-FAPI).A sustained reduction in FAPI uptake predicts the regression of fibrotic components, which is crucial for assessing long-term prognosis and organ function recovery.Furthermore, combined with the PET index (> 1.5 indicating high recurrence risk) proposed by Liu et al. [ 35 ] , FAPI can serve not only to monitor current fibrotic activity but also as a prognostic biomarker to guide the development of long-term maintenance therapy strategies. 3.4. Limitations This study has certain limitations.First, due to the low incidence of IgG4-RD and the fact that FAPI imaging technology is still in the clinical dissemination phase, the number of head-to-head comparative studies meeting inclusion criteria was limited (only 3), with a small overall sample size (n = 90).This limited the statistical power to conduct more in-depth subgroup analyses (e.g., different organ subgroups or different fibrosis stages).Second, significant heterogeneity existed among the included studies; some were of retrospective design, which may introduce selection bias.Additionally, although all patients had a definitive diagnosis, it was practically difficult to histopathologically verify every PET/CT-positive lesion; the characterization of some small lesions relied on clinical follow-up, which may introduce some bias in the assessment of diagnostic efficacy.Finally, this study mainly focused on a cross-sectional comparison of diagnostic efficacy and lacked longitudinal data regarding FAPI in monitoring treatment response and long-term prognostic assessment, which still requires further verification by future large-sample, multicenter prospective studies. 4. Conclusion In summary, this systematic review and pooled analysis demonstrates that 68 Ga-FAPI PET/CT possesses unique clinical value in the diagnosis and assessment of IgG4-related disease (IgG4-RD).Benefiting from its specific targeting mechanism for fibroblast activation protein (FAP) and extremely low abdominal physiological background uptake, 68 Ga-FAPI exhibits sensitivity and image contrast significantly superior to traditional 18 F-FDG PET/CT in detecting parenchymal organ involvement, such as in the pancreas, bile ducts, and salivary glands.However, in the assessment of lymph node lesions, 18 F-FDG retains an irreplaceable advantage.This finding suggests that the two tracers reflect different pathophysiological processes of IgG4-RD—fibrotic activity and inflammatory cell infiltration, respectively—indicating that they are not simple substitutes for each other but rather complementary in clinical application. 68 Ga-FAPI holds promise as a powerful complementary imaging tool, particularly suitable for characterizing fibrosis-dominant lesions, detecting small occult lesions, and accurately staging the systemic extent of the disease. Declarations • Ethics approval and consent to participate : As this study is a systematic review and meta-analysis of publicly available data, it did not involve human or animal subjects. Therefore, ethical approval and informed consent were not required. • Consent for publication : Not applicable. This study did not involve individual patient data or images. • Availability of data and material : All data used in this study were extracted from publicly available peer-reviewed articles indexed in PubMed, Embase, and Web of Science. The original data supporting the pooled analysis are available within the article and its supplementary materials. Raw data from individual studies can be accessed through the respective publications. • Competing interests : The authors declare no competing interests. • Funding : This work was supported by the Guiding Scientific Research Project of Shiyan Science and Technology Bureau (Grant No. 25Y158). • Authors' contributions : ZJ (corresponding author) conceptualized the study, performed the literature search.HQF is responsible for drafting the initial version of the article. CX is responsible for the production, acquisition, and analysis of images. • Acknowledgements : Not applicable. The authors wish to thank the investigators whose studies contributed to this analysis. References Inoue D, Yoshida K, Yoneda N, et al. IgG4-related disease: dataset of 235 consecutive patients. Medicine. 2015;94(15):e680. 10.1097/MD.0000000000000680 . Adam Z, Zeman D, Čermák A, et al. [IgG4-related disease. Clinical manifestation differential diagnosis and recent International Diagnostic Criteria for IgG4-related disease]. Vnitr Lek. 2022;68(E–5):4–19. 10.36290/vnl.2022.070 . Zhao Z, Wang Y, Guan Z et al. Utility of FDG-PET/CT in the diagnosis of IgG4-related diseases. CLIN EXP RHEUMATOL. 2016; 34 (1): 119 – 25. PMID: 26842851. Ebbo M, Grados A, Guedj E, et al. Usefulness of 2-[ 18 F]-fluoro-2-deoxy-D-glucose-positron emission tomography/computed tomography for staging and evaluation of treatment response in IgG4-related disease: a retrospective multicenter study. ARTHRIT CARE RES. 2014;66(1):86–96. 10.1002/acr.22058 . Johnsen RH, Christensen KB, Shaker SB, et al. [Fibroblast activation protein inhibitor PET for monitoring fibrotic diseases]. Ugeskr Laeger. 2025;187(45). 10.61409/V04250306 . Kalantari F, Hörmann AA, Pokarowski M, et al. Fibroblast Activation Protein Inhibitor (FAPI)-Radioligand PET/CT in the Assessment of Nononcological Diseases: A Narrative Review. ACS PHARMACOL TRANSL. 2025;8(12):4193–213. 10.1021/acsptsci.4c00641 . Hu K, Wang L, Wu H, et al. [ 18 F]FAPI-42 PET imaging in cancer patients: optimal acquisition time, biodistribution, and comparison with [ 68 Ga]Ga-FAPI-04. EUR J NUCL MED MOL I. 2021;49(8):2833–43. 10.1007/s00259-021-05646-z . Luo Y, Pan Q, Yang H, et al. Fibroblast Activation Protein-Targeted PET/CT with 68 Ga-FAPI for Imaging IgG4-Related Disease: Comparison to 18 F-FDG PET/CT. J NUCL MED. 2020;62(2):266–71. 10.2967/jnumed.120.244723 . Lartey DA, Schilder LA, Zwezerijnen GJC, et al. FAPi PET/CT Imaging to Identify Fibrosis in Immune-Mediated Inflammatory Diseases. Biomedicines. 2025;13(4). 10.3390/biomedicines13040775 . Wan L, Sun C, Liang J, et al. Volume-Based Quantitative Measurement of [ 18 F]AlF-NOTA-FAPI-04 PET/CT Uptake Reflects the Disease Activity of IgG4-Related Disease. MOL IMAGING BIOL. 2024;26(5):753–60. 10.1007/s11307-024-01928-8 . Kaplan İ, Kepenek F, Güzel Y, et al. The Role of 68 Ga FAPI-04 and 18 F-FDG PET/CT in Detecting Liver Metastases in Different Types of Cancer. NUKLEARMED-NUCL MED. 2023;62(4):252–9. 10.1055/a-2127-7699 . Mori Y, Dendl K, Cardinale J, et al. FAPI PET: Fibroblast Activation Protein Inhibitor Use in Oncologic and Nononcologic Disease. Radiology. 2023;306(2):e220749. 10.1148/radiol.220749 . Sharma P, Singh SS, Gayana S. Fibroblast Activation Protein Inhibitor PET/CT: A Promising Molecular Imaging Tool. CLIN NUCL MED. 2021;46(3):e141–50. 10.1097/RLU.0000000000003489 . Abdlkadir AS, Ardalan Z, Scott AM, et al. Diagnostic utility of FDG and FAPI PET imaging in crohn's disease: a systematic review and meta-analysis. EUR J NUCL MED MOL I. 2025;53(3):1434–44. 10.1007/s00259-025-07608-1 . Desaulniers M, Rousseau É, Pabst KM. Clinical and Research Applications of FAPI Tracers: A Review. BRIT J RADIOL. 2025. 10.1093/bjr/tqaf020 . Li Y, Zhang J, Shen T, et al. [IgG4-related diseases: A comprehensive review]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2019;35(1):83–8. PMID: 30914118. Mori Y, Giesel FL, Györfi AH, et al. [FAPI-PET-CT for quantification of the tissue response in rheumatic diseases]. Z RHEUMATOL. 2024;83(6):455–9. 10.1007/s00393-024-01536-5 . Zhang Y, Wang J, Li M, et al. The different manifestations of 18 F-FDG PET/CT and 68 Ga-FAPI-04 PET/CT in evaluation of the steroid therapy response for IgG4-related disease: A case report. Front Immunol. 2024;15:1354093. 10.3389/fimmu.2024.1354093 . Giesel FL, Kratochwil C, Lindner T, et al. 68 Ga-FAPI PET/CT: Biodistribution and Preliminary Dosimetry Estimate of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various Cancers. J NUCL MED. 2018;60(3):386–92. 10.2967/jnumed.118.215913 . Sadeghpour S, Aghaee A, Ahmadzadehfar H, et al. Revealing the hidden: A systematic review and meta-analysis of FAPI-based tracers imaging for brain metastatic lesions. EUR J NUCL MED MOL I. 2025;53(3):1419–33. 10.1007/s00259-025-07576-6 . Manuppella F, Pisano G, Taralli S, et al. Diagnostic Performances of PET/CT Using Fibroblast Activation Protein Inhibitors in Patients with Primary and Metastatic Liver Tumors: A Comprehensive Literature Review. Int J Mol Sci. 2024;25(13). 10.3390/ijms25137197 . Novruzov E, Dendl K, Ndlovu H, et al. Head-to-head Intra-individual Comparison of [ 68 Ga]-FAPI and [ 18 F]-FDG PET/CT in Patients with Bladder Cancer. MOL IMAGING BIOL. 2022;24(4):651–8. 10.1007/s11307-022-01715-3 . Tang R, Liu M, Shu Q, et al. Performance of fibroblast activating protein inhibitor PET imaging for pancreatic neoplasms assessment: a systematic review and meta-analysis. EUR RADIOL. 2024;34(12):7804–12. 10.1007/s00330-024-10843-z . Zhang J, He Q, Jiang S, et al. [ 18 F]FAPI PET/CT in the evaluation of focal liver lesions with [ 18 F]FDG non-avidity. EUR J NUCL MED MOL I. 2022;50(3):937–50. 10.1007/s00259-022-06022-1 . Gunasekaran G, Amalachandran J. 68 Ga-FAPI PET/CT versus 18 F-FDG PET/CT: Differentiating Metastatic Disease and Reactive Lymph Nodes in a Case of Carcinoma of Breast/Acquired Immunodeficiency Syndrome. WORLD J NUCL MED. 2024;23(3):217–9. 10.1055/s-0044-1787718 . Westermann J, Bode U, Sahle A, et al. Naive, effector, and memory T lymphocytes efficiently scan dendritic cells in vivo: contact frequency in T cell zones of secondary lymphoid organs does not depend on LFA-1 expression and facilitates survival of effector T cells. J IMMUNOL. 2005;174(5):2517–24. 10.4049/jimmunol.174.5.2517 . Giesel FL, Kratochwil C, Lindner T, et al. 68 Ga-FAPI PET/CT: Biodistribution and Preliminary Dosimetry Estimate of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various Cancers. J Nucl Med. 2019;60(3):386–92. 10.2967/jnumed.118.215913 . Demmert TT, Pomykala KL, Lanzafame H, et al. Oncologic Staging with 68 Ga-FAPI PET/CT Demonstrates a Lower Rate of Nonspecific Lymph Node Findings Than 18 F-FDG PET/CT. J NUCL MED. 2023;64(12):1906–9. 10.2967/jnumed.123.265751 . Oksuzoglu K, Ozen G, Inanir S, et al. Flip-flop phenomenon in systemic sclerosis on fluorodeoxyglucose positron emission tomography/computed tomography. INDIAN J NUCL MED. 2015;30(4):350–1. 10.4103/0972-3919.164018 . Chen X, Wang S, Lai Y, et al. Fibroblast Activation Protein and Glycolysis in Lymphoma Diagnosis: Comparison of 68 Ga-FAPI PET/CT and 18 F-FDG PET/CT. J Nucl Med. 2023;64(9):1399–405. 10.2967/jnumed.123.265530 . Ozawa Y, Yamamoto, Hiroshi, Yasuo M, et al. A comparison of the features of fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) between IgG4-related disease with bilateral hilar lymphadenopathy and sarcoidosis. Nagoya J Med Sci. 2020;82(1):101–11. 10.18999/nagjms.82.1.101 . Taniguchi Y, Ode K, Hirose K et al. AB0929 The Serum Levels of Cholinesterase and Total Cholesterol PREDICT the Existence or Latency of Multiple Organs' Involvements in Japanese Patients with Igg4-Related Disease ANN RHEUM DIS. 2014; 73 (Suppl 2): 1107.3–1107. 10.1136/annrheumdis-2014-eular.4250 Taniguchi Y, Ogata K, Shimamura Y, et al. Splenic lesion of IgG4-related disease in FDG-PET/CT Case Rep. Intern Med. 2014;1(2). 10.5430/crim.v1n2p150 . Kratochwil C, Flechsig P, Lindner T, et al. 68 Ga-FAPI PET/CT: Tracer Uptake in 28 Different Kinds of Cancer. J Nucl Med. 2019;60(6):801–5. 10.2967/jnumed.119.227967 . Liu S, Pan Q, Zhang H, et al. Differences in Fibroinflammatory Activity Shown on 68 Ga-FAPI-04 and 18 F-FDG PET/CT in the Two Subtypes of IgG4-Related Disease. J Nucl Med. 2025;66(4):634–40. 10.2967/jnumed.124.268943 . Schmidkonz C, Rauber, Simon, Atzinger A, et al. Disentangling inflammatory from fibrotic disease activity by fibroblast activation protein imaging. ANN RHEUM DIS. 2020;79(11):1485–91. 10.1136/annrheumdis-2020-217408 . Tang Y, Li Y, Zhang X, et al. Diagnostic performance of F-18 FDG PET/CT in differentiating autoimmune pancreatitis from pancreatic cancer: a systemic review and meta-analysis. Ann Nucl Med. 2024;38(6):455–65. 10.1007/s12149-024-01932-w . Pan Q, Luo Y, Zhang W. Recurrent Immunoglobulin G4-Related Disease Shown on 18 F-FDG and 68 Ga-FAPI PET/CT. CLIN NUCL MED. 2020;45(4):312–3. 10.1097/RLU.0000000000002919 . Ji H, Song, Xiangming, Lv X et al. [ 68 Ga]FAPI PET for Imaging and Treatment Monitoring in a Preclinical Model of Pulmonary Fibrosis: Comparison to [ 18 F]FDG PET and CT. Pharmaceuticals (Basel). 2024; 17 (6): 10.3390/ph17060726 Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major Revision 12 Apr, 2026 Reviewers agreed at journal 01 Mar, 2026 Reviewers invited by journal 27 Feb, 2026 Editor assigned by journal 27 Feb, 2026 First submitted to journal 26 Feb, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8932863","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":598266179,"identity":"594fae28-a99e-416d-9fc3-51d13d4da31f","order_by":0,"name":"Xue CAI","email":"","orcid":"","institution":"Sinopharm Dongfeng General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xue","middleName":"","lastName":"CAI","suffix":""},{"id":598266180,"identity":"b2693093-0aa8-433b-bf02-f73a7d917c8b","order_by":1,"name":"Qingfan HAO","email":"","orcid":"","institution":"Shiyan Renmin Hospital","correspondingAuthor":false,"prefix":"","firstName":"Qingfan","middleName":"","lastName":"HAO","suffix":""},{"id":598266181,"identity":"de341b47-0fb4-48d6-98db-33618f051475","order_by":2,"name":"Jian ZHANG","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA4klEQVRIiWNgGAWjYBACNvbmAwYJBjZy/PztBx8kVNQQ1sLHcyyh4ENBmrHkjDPJBg/OHCOsRU4iR+HjjA+HEzccSDCTfNjCTITDeM4wbuYxYGbccOBAWkViAxsDf3t3AgG/9B425jFgY5Y83HjsRuIOGQaJM2c3ELDlXBpQCw8bH9CWG4ln2BgMJHIJaJHIMf/NYyDBwwD0S0FiGzNRWgwMZxgYSAgAtTAQpwUYyAYfgDEDCmSJhDPHeAj6Rb4dFJV//tf3A6Py44+KGjn+9l78WjAAD2nKR8EoGAWjYBRgBQB6kU3yEN0ZEAAAAABJRU5ErkJggg==","orcid":"","institution":"Sinopharm Dongfeng General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Jian","middleName":"","lastName":"ZHANG","suffix":""}],"badges":[],"createdAt":"2026-02-21 10:53:49","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8932863/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8932863/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":104176329,"identity":"e5d4899b-7d65-4080-a379-97fe2d3e7d2c","added_by":"auto","created_at":"2026-03-08 16:37:27","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":298535,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePRISMA 2020 flow diagram illustrating the literature search and study selection process\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"PRISMA11.png","url":"https://assets-eu.researchsquare.com/files/rs-8932863/v1/656c3ff7c0610c88380a1ae4.png"},{"id":104404800,"identity":"7f93de19-d113-4345-8478-3f409d059c69","added_by":"auto","created_at":"2026-03-11 12:21:07","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":143563,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSummary of the methodological quality of the included studies according to the QUADAS-2 tool\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"zlfx.png","url":"https://assets-eu.researchsquare.com/files/rs-8932863/v1/5efe608066153c942fbfd6e7.png"},{"id":104176327,"identity":"bbb2f3ca-595e-40b8-a7ba-3b023209b1c8","added_by":"auto","created_at":"2026-03-08 16:37:27","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":130557,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eHead-to-head comparison of quantitative parameters.Panel A shows that\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003csup\u003e\u003cstrong\u003e68\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eGa-FAPI has significantly higher SUVmax values than \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FDG in lymph nodes, salivary glands, and the pancreas (\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e\u0026lt;0.0001), indicating stronger lesion uptake. Panel B demonstrates that \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e68\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eGa-FAPI yields significantly higher target-to-background ratios (TBR) in the pancreas and salivary glands (\u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eP\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e\u0026lt;0.0001), suggesting superior lesion-to-background contrast. Panel C reveals that \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e68\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eGa-FAPI detects significantly more lesions than \u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e18\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003eF-FDG \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003e(P\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e\u0026lt;0.0001), highlighting its advantage in lesion detection rates.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"resule.png","url":"https://assets-eu.researchsquare.com/files/rs-8932863/v1/84e28a670fc16635713b81a1.png"},{"id":106723630,"identity":"ebb57637-6317-4385-b1a6-fdba25ec8fde","added_by":"auto","created_at":"2026-04-12 18:09:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2007509,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8932863/v1/c8093777-11ac-499e-9272-ab18849197bc.pdf"}],"financialInterests":"","formattedTitle":"Complementary Roles of 68Ga-FAPI and 18F-FDG PET/CT in Evaluating IgG4-Related Disease: A Systematic Review and Pooled Analysis","fulltext":[{"header":"2. Background","content":"\u003cp\u003eIgG4-related disease (IgG4-RD) is a rare immune-mediated fibroinflammatory condition capable of involving multiple organs, characterized by lymphoplasmacytic infiltration rich in IgG4-positive plasma cells, storiform fibrosis, and obliterative phlebitis \u003csup\u003e[1]\u003c/sup\u003e.The diagnosis of IgG4-RD poses challenges and often requires a comprehensive assessment combining serology, imaging, and pathology \u003csup\u003e[2]\u003c/sup\u003e.Imaging techniques are crucial for identifying involved organs, guiding biopsies, and monitoring treatment response \u003csup\u003e[3]\u003c/sup\u003e.Although \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT, a commonly used molecular imaging method, can visualize metabolically active lesions throughout the body, it is associated with issues of false negatives and false positives in IgG4-RD \u003csup\u003e[4]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eRecently, \u003csup\u003e68\u003c/sup\u003eGa-FAPI PET/CT, a novel imaging technique targeting fibroblast activation protein (FAP), has demonstrated potential in fibrotic diseases \u003csup\u003e[5]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe pathological essence of IgG4-RD is immune-inflammation-driven fibrosis, wherein fibroblast activation protein (FAP) is highly expressed in activated fibroblasts and serves as a key marker of fibrotic activity.\u003csup\u003e68\u003c/sup\u003eGa-labeled FAPI inhibitors (\u003csup\u003e68\u003c/sup\u003eGa-FAPI), by specifically targeting FAP, allow for the direct visualization of active fibrotic regions, overcoming the metabolism-dependent limitations of FDG \u003csup\u003e[6]\u003c/sup\u003e, and are characterized by high specific binding to FAP, low background noise, rapid blood clearance, and favorable biosafety \u003csup\u003e[7]\u003c/sup\u003e. Studies have shown that FAP is significantly upregulated in fibroblasts within IgG4-RD involved organs, particularly in the pancreas, biliary tract, and salivary glands \u003csup\u003e[8]\u003c/sup\u003e. Furthermore, FAPI can distinguish active fibrosis from old scars, as the latter do not uptake FAPI due to fibroblast inactivation \u003csup\u003e[9]\u003c/sup\u003e.Theoretically, FAPI PET/CT can also assess the degree of fibrosis by quantifying FAP expression levels, providing an objective basis for disease staging \u003csup\u003e[10]\u003c/sup\u003e. Compared with FDG, FAPI exhibits a higher target-to-background ratio (TBR), showing distinct advantages especially in organs with high physiological uptake such as the liver and pancreas \u003csup\u003e[11]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThis study aims to provide evidence-based medical evidence for clinical selection by directly comparing (head-to-head) the lesion detection rates, uptake intensity, and image contrast of the two tracers in IgG4-RD through a systematic review and meta-analysis.\u003c/p\u003e"},{"header":"3. Main Text","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Materials and Methods\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003e3.1.1. Study Protocol and Registration\u003c/h2\u003e \u003cp\u003e This systematic review and pooled analysis was conducted in strict accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement.The study protocol was designed to meet high methodological standards for diagnostic accuracy assessment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section3\"\u003e \u003ch2\u003e3.1.2. Search Strategy and Data Sources\u003c/h2\u003e \u003cp\u003eWe performed a comprehensive systematic literature search in three major electronic databases: PubMed, Embase, and Web of Science.The search spanned from the inception of each database to February 1, 2026.\u003c/p\u003e \u003cp\u003eTo ensure a broad and comprehensive retrieval of relevant studies, the search strategy combined Medical Subject Headings (MeSH) and free-text keywords, including but not limited to \"IgG4-Related Disease,\" \"Fibroblast Activation Protein Inhibitor,\" \"FAPI,\" \"FDG,\" and \"PET/CT\".The search was restricted to articles published in English.We refined the search results using Boolean operators (AND, OR).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section3\"\u003e \u003ch2\u003e3.1.3. Inclusion Criteria and Study Selection\u003c/h2\u003e \u003cp\u003eStudies meeting the following criteria were included in this review: (1) comparative studies or clinical trials involving patients with histopathologically or clinically confirmed IgG4-RD; (2) subjects underwent a head-to-head comparison of \u003csup\u003e68\u003c/sup\u003eGa-FAPI and \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT; and (3) sufficient quantitative data (e.g., SUVmax, lesion detection rate) were reported to allow for pooled analysis.Case reports, reviews, editorials, conference abstracts, and non-comparative studies were excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section3\"\u003e \u003ch2\u003e3.1.4. Data Extraction and Quality Assessment\u003c/h2\u003e \u003cp\u003eLiterature screening and data extraction were independently performed by two investigators (Q.F.H. and X.C. ).Any discrepancies regarding study inclusion or data extraction were resolved through consensus via group discussion or, if necessary, consultation with a third senior reviewer.The methodological quality and potential risk of bias of the included studies were rigorously assessed using QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2), the recommended standard tool for diagnostic accuracy evaluation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section3\"\u003e \u003ch2\u003e3.1.5. Statistical Analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses and graph plotting were performed using GraphPad Prism software (Version 9.0, GraphPad Software, San Diego, CA, USA). Continuous variables (such as maximum standardized uptake value [SUVmax] and target-to-background ratio [TBR]) were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD).Differences in quantitative uptake values between \u003csup\u003e68\u003c/sup\u003eGa-FAPI and \u003csup\u003e18\u003c/sup\u003eF-FDG were evaluated using the paired Student's t-test or Wilcoxon matched-pairs signed-rank test, depending on the normality of the data distribution.In the assessment of lesion detection capability, categorical data were expressed as frequencies (n) and percentages (%). Differences in lesion detection rates between the two tracers were analyzed using the Chi-square test or Fisher's exact test. A \u003cem\u003eP\u003c/em\u003e-value of less than 0.05 was considered statistically significant (*\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, **\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01, ***\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, ****\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Results\u003c/h2\u003e \u003cdiv id=\"Sec10\" class=\"Section3\"\u003e \u003ch2\u003e3.2.1. Literature Search Results\u003c/h2\u003e \u003cp\u003eThe initial search identified a total of 169 relevant articles across the three major databases (PubMed, Embase, and Web of Science).After automatic de-duplication using reference management software supplemented by manual verification, 70 duplicate records were removed, leaving 99 articles for the preliminary screening phase.Following a rigorous screening of titles and abstracts, the majority of articles unrelated to the study topic, reviews, case reports, and animal studies were excluded, leaving 17 articles for full-text assessment.Through careful reading and strict review of the full texts, studies with non-head-to-head comparison designs, lack of key quantitative data, or overlapping patient cohorts were further excluded. Finally, a total of 3 high-quality studies meeting all inclusion and exclusion criteria (Luo et al., Liu et al., Schmidkonz et al.) were included in this systematic review and pooled analysis.The detailed literature screening and inclusion process is shown in Fig.\u0026nbsp;1.(\u003cb\u003eFig.\u0026nbsp;1\u003c/b\u003e)\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;1 PRISMA 2020 flow diagram illustrating the literature search and study selection process\u003c/b\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003e3.2.2. Methodological Quality Assessment\u003c/h2\u003e \u003cp\u003eThe risk of bias and applicability of the 3 included studies (Luo et al., Liu et al., Schmidkonz et al.) were assessed using the QUADAS-2 tool, with results indicating a high overall methodological quality of the included studies \u003cb\u003e(Fig.\u0026nbsp;2\u003c/b\u003e ).\u003c/p\u003e \u003cp\u003e \u003cb\u003eFigure\u0026nbsp;2 Summary of the methodological quality of the included studies according to the QUADAS-2 tool\u003c/b\u003e \u003c/p\u003e \u003cp\u003eIn the \"Patient Selection\" domain, all studies explicitly described inclusion criteria and avoided case-control design bias, thus being rated as low risk.In the \"Index Test\" and \"Reference Standard\" domains, as all patients underwent head-to-head comparisons of \u003csup\u003e68\u003c/sup\u003eGa-FAPI and \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT within a short interval, and diagnostic results were referenced against histopathology or clinical follow-up with proper blinding, no significant measurement bias was detected.Additionally, no attrition or inappropriate exclusion was observed in any study regarding \"Flow and Timing\".\u003c/p\u003e \u003cp\u003eIn summary, all included studies were evaluated as \"Low Risk\" in terms of bias risk and clinical applicability, with no \"High Risk\" or \"Unclear\" items found, indicating a robust and reliable evidentiary basis for this systematic review.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section3\"\u003e \u003ch2\u003e3.2.3. Study Characteristics and Baseline Data\u003c/h2\u003e \u003cp\u003eThe 3 studies finally included in this systematic review and pooled analysis (Luo et al., Liu et al., Schmidkonz et al.) comprised a total of 90 patients with histopathologically or clinically confirmed IgG4-related disease (IgG4-RD).All patients completed head-to-head comparisons of \u003csup\u003e68\u003c/sup\u003eGa-FAPI and \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT within a short time interval.Among these 3 studies, one was a prospective cohort design (Luo et al., 2020), and two were retrospective comparative studies (Liu et al., 2025; Schmidkonz et al., 2020).The study locations were distributed in China (2 studies) and Germany (1 study), representing data from Asian and European populations, respectively.The median age of patients ranged from 58 to 61 years, with a higher proportion of male patients than females (male:female ratio approximately 2:1), consistent with the epidemiological characteristics of IgG4-RD.The study by Liu et al. further subdivided patients into proliferative and fibrotic subgroups. Detailed baseline characteristics of the included studies are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e )\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eBaseline information of comparative studies enrolled in the meta-analysis\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReferences\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDesign\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePatients\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eImaging examinations\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eAge\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNo. of patients\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLuo et al.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProspective cohort study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eHistopathologically or clinically diagnosed IgG4-RD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003csup\u003e68\u003c/sup\u003eGa-FAPI-04 PET/CT\u003c/p\u003e \u003cp\u003e\u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian age 61\u003c/p\u003e \u003cp\u003e(range 35\u0026ndash;78)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e26 (19 m; 7 f)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eLiu et al.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eComparative study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eNewly diagnosed IgG4-RD (Proliferative \u0026amp; Fibrotic subtypes)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003csup\u003e68\u003c/sup\u003eGa-FAPI-04 PET/CT\u003c/p\u003e \u003cp\u003e\u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian age 58\u003c/p\u003e \u003cp\u003e(range 31\u0026ndash;82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e37 (25 m; 12 f)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSchmidkonz et al.\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eComparative study\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIgG4-RD patients with histopathological confirmation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u003csup\u003e68\u003c/sup\u003eGa-FAPI-04 PET/CT\u003c/p\u003e \u003cp\u003e\u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eMedian age 60\u003c/p\u003e \u003cp\u003e(range 40\u0026ndash;80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e27 (18 m; 9 f)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e \u003cb\u003eBaseline information of comparative studies enrolled in the meta-analysis\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003e3.2.4. Data Pooled Analysis\u003c/h2\u003e \u003cp\u003eAlthough this systematic review included 3 studies with 90 patients, due to differences in data reporting formats, only 2 studies (Luo et al. and Liu et al., totaling 63 patients) provided compatible Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD data and were thus included in the quantitative pooled analysis (Meta-analysis) for SUVmax.The study by Schmidkonz et al. (n\u0026thinsp;=\u0026thinsp;27), which reported only medians and ranges, could not be directly statistically pooled and was therefore included only for qualitative description, excluded from quantitative graphical analysis.Given the small number of included studies, we employed a sample-size weighted mean to calculate the pooled SUVmax and TBR.(\u003cb\u003eFig .3\u003c/b\u003e )\u003c/p\u003e \u003cp\u003e \u003cb\u003eFig .3 Head-to-head comparison of quantitative parameters.Panel A shows that\u003c/b\u003e \u003c/p\u003e \u003cp\u003e \u003csup\u003e \u003cb\u003e68\u003c/b\u003e \u003c/sup\u003e \u003cb\u003eGa-FAPI has significantly higher SUVmax values than\u003c/b\u003e \u003csup\u003e\u003cb\u003e18\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FDG in lymph nodes, salivary glands, and the pancreas (\u003c/b\u003e\u003cb\u003eP\u003c/b\u003e\u0026thinsp;\u003cb\u003e\u0026lt;\u0026thinsp;0.0001), indicating stronger lesion uptake. Panel B demonstrates that\u003c/b\u003e \u003csup\u003e\u003cb\u003e68\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eGa-FAPI yields significantly higher target-to-background ratios (TBR) in the pancreas and salivary glands (\u003c/b\u003e\u003cb\u003eP\u003c/b\u003e\u0026thinsp;\u003cb\u003e\u0026lt;\u0026thinsp;0.0001), suggesting superior lesion-to-background contrast. Panel C reveals that\u003c/b\u003e \u003csup\u003e\u003cb\u003e68\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eGa-FAPI detects significantly more lesions than\u003c/b\u003e \u003csup\u003e\u003cb\u003e18\u003c/b\u003e\u003c/sup\u003e\u003cb\u003eF-FDG\u003c/b\u003e \u003cb\u003e(P\u003c/b\u003e\u0026thinsp;\u003cb\u003e\u0026lt;\u0026thinsp;0.0001), highlighting its advantage in lesion detection rates.\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section3\"\u003e \u003ch2\u003e3.2.5. Semi-quantitative Uptake Intensity\u003c/h2\u003e \u003cp\u003ePooled analysis based on the two mergeable head-to-head comparative studies (Luo et al. and Liu et al., totaling 63 patients) revealed significant differences in the uptake patterns of \u003csup\u003e68\u003c/sup\u003eGa-FAPI and \u003csup\u003e18\u003c/sup\u003eF-FDG across different involved organs (Fig.\u0026nbsp;3-A).In involved pancreatic parenchyma, the mean SUVmax of \u003csup\u003e68\u003c/sup\u003eGa-FAPI was significantly higher than that of \u003csup\u003e18\u003c/sup\u003eF-FDG (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating that FAPI possesses higher activity in reflecting pancreatic fibroinflammation.Similarly, in submandibular/parotid gland lesions, \u003csup\u003e68\u003c/sup\u003eGa-FAPI also exhibited significantly higher radiotracer uptake (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).However, an opposite trend was observed in lymph node lesions: the uptake value of \u003csup\u003e18\u003c/sup\u003eF-FDG was significantly higher than that of \u003csup\u003e68\u003c/sup\u003eGa-FAPI (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).This organ-specific \"flip-flop phenomenon\" suggests that the two tracers may reflect the metabolic characteristics of different pathological components (inflammation vs. fibrosis) of IgG4-RD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section3\"\u003e \u003ch2\u003e3.2.6. Lesion Detection Capability\u003c/h2\u003e \u003cp\u003eIn the assessment of lesion detection capability, \u003csup\u003e68\u003c/sup\u003eGa-FAPI demonstrated sensitivity superior to that of \u003csup\u003e18\u003c/sup\u003eF-FDG (Fig.\u0026nbsp;3-B).Based on data analysis from a representative study (Luo et al.), \u003csup\u003e68\u003c/sup\u003eGa-FAPI PET/CT detected a total of 136 IgG4-RD-related lesions, whereas concurrent \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT detected only 78 lesions.The overall lesion detection rate of \u003csup\u003e68\u003c/sup\u003eGa-FAPI was significantly higher than that of \u003csup\u003e18\u003c/sup\u003eF-FDG (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). \u003csup\u003e68\u003c/sup\u003eGa-FAPI was able to identify more involved organs missed by \u003csup\u003e18\u003c/sup\u003eF-FDG, with particularly evident detection advantages in pancreatic, biliary, and certain retroperitoneal fibrosis lesions, thereby more accurately assessing the pan-scan extent of the disease.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section3\"\u003e \u003ch2\u003e3.2.7. Image Contrast and Target-to-Background Ratio (TBR)\u003c/h2\u003e \u003cp\u003eTo evaluate image quality and lesion visualization, we compared the target-to-background ratio (TBR) of the two tracers (Fig.\u0026nbsp;3-C).Benefiting from extremely low abdominal background uptake, \u003csup\u003e68\u003c/sup\u003eGa-FAPI demonstrated superior image contrast in parenchymal organs. In pancreatic lesions, the mean TBR of \u003csup\u003e68\u003c/sup\u003eGa-FAPI reached \u003csup\u003e18\u003c/sup\u003e.02\u0026thinsp;\u0026plusmn;\u0026thinsp;13.91, which was more than 5 times that of \u003csup\u003e18\u003c/sup\u003eF-FDG (3.44\u0026thinsp;\u0026plusmn;\u0026thinsp;2.05), a difference of high statistical significance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).Similarly, in salivary gland lesions, the TBR of \u003csup\u003e68\u003c/sup\u003eGa-FAPI (9.92\u0026thinsp;\u0026plusmn;\u0026thinsp;5.61) was significantly higher than that of \u003csup\u003e18\u003c/sup\u003eF-FDG (3.12\u0026thinsp;\u0026plusmn;\u0026thinsp;1.51, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).These results indicate that \u003csup\u003e68\u003c/sup\u003eGa-FAPI provides a higher signal-to-noise ratio, rendering lesion boundaries clearer and facilitating the identification of small lesions.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section3\"\u003e \u003ch2\u003e3.2.8. Heterogeneity in Treatment Response Monitoring\u003c/h2\u003e \u003cp\u003eBased on the analysis of longitudinal follow-up data from the study by Schmidkonz et al., the two tracers exhibited significant biological differences in assessing treatment response.Following anti-inflammatory therapy (e.g., rituximab or glucocorticoids), the vast majority of lesions with high baseline uptake showed a significant reduction or even disappearance of metabolic activity on \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT, suggesting effective control of inflammatory infiltration.However, within the same group of lesions, \u003csup\u003e68\u003c/sup\u003eGa-FAPI radiotracer uptake showed varying degrees of persistence after treatment; in some involved organs (particularly the pancreas and retroperitoneal regions), the FAPI signal remained at a relatively high level despite some attenuation.This phenomenon of \"FDG-negative but FAPI-persistent\" was corroborated at the immunofluorescence level, indicating that while treatment successfully cleared or suppressed lymphocytes (CD45+), it failed to fully reverse activated fibroblasts (FAP+) and the associated fibrotic remodeling process.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Discussion\u003c/h2\u003e \u003cdiv id=\"Sec19\" class=\"Section3\"\u003e \u003ch2\u003e3.3.1. Pathophysiological Mechanisms of FAPI Advantages\u003c/h2\u003e \u003cp\u003eThe core mechanism of action of fibroblast activation protein inhibitors (FAPI) relies on their high specific binding to fibroblast activation protein (FAP).FAP is highly expressed on the surface of activated fibroblasts, being significantly upregulated particularly in cancer-associated fibroblasts (CAFs) within the tumor microenvironment, wound healing, and inflammatory fibrosis processes \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. FAPI tracers achieve precise targeting of activated fibroblasts by covalently binding to the catalytic site of FAP \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. A systematic review on Crohn's disease by Abdlkadir, AS et al. \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e showed that FAPI PET achieved a detection rate of 99% for intestinal wall fibrosis, with sensitivity and specificity of 92% and 93% respectively, significantly superior to the 76% and 81% of [\u003csup\u003e18\u003c/sup\u003eF]FDG.This mechanism enables FAPI PET to directly visualize active fibrotic regions, reflecting the matrix remodeling process more specifically than metabolism-dependent \u003csup\u003e18\u003c/sup\u003eF-FDG \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e.IgG4-related disease (IgG4-RD) is a unique fibroinflammatory condition whose disease progression involves the synergistic action of immune dysregulation and fibrosis \u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e.As the disease progresses, fibrosis gradually replaces inflammation as the dominant pathological change, leading to sclerosing organ enlargement and dysfunction.This dynamic evolution explains the utility of FAPI in IgG4-RD: it can capture inflammation-related fibrosis in the early stages and assess fibrotic burden in the late stages to guide corticosteroid therapy \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]\u003c/sup\u003e. Research by Mori, Y et al. \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e on IgG4-related disease concluded that FAPI uptake correlates significantly with histological fibrosis grading (r\u0026thinsp;=\u0026thinsp;0.54\u0026ndash;0.57, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and can predict treatment response.In cases of IgG4-related pancreatitis, FAPI PET clearly demonstrated diffuse high uptake in the pancreas (SUVmax\u0026thinsp;=\u0026thinsp;8.8), whereas \u003csup\u003e18\u003c/sup\u003eF-FDG showed mild uptake (SUVmax\u0026thinsp;=\u0026thinsp;2.5), with pathology ultimately confirming fibrosis-dominant lesions \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eInterference from high-uptake organs is a critical factor affecting diagnostic accuracy, and the low-background characteristic of FAPI effectively addresses this challenge.In conventional \u003csup\u003e18\u003c/sup\u003eF-FDG PET, high physiological uptake in the brain (SUVmax\u0026thinsp;=\u0026thinsp;11.01), liver (SUVmean\u0026thinsp;=\u0026thinsp;2.77), and urinary system often obscures adjacent lesions, such as brain metastases or small intrahepatic lesions \u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e.In contrast, FAPI uptake in normal brain tissue is extremely low (SUVmax\u0026thinsp;=\u0026thinsp;0.32), increasing the detection rate of intracranial metastases to 87.9%, far exceeding the 46.3% of \u003csup\u003e18\u003c/sup\u003eF-FDG \u003csup\u003e[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]\u003c/sup\u003e.In the liver, the background uptake of FAPI (SUVmean\u0026thinsp;=\u0026thinsp;1.69) is significantly lower than that of \u003csup\u003e18\u003c/sup\u003eF-FDG, increasing the target-to-background ratio (TBR) of intrahepatic lesions from 2.8 to 5.1 and boosting detection sensitivity for small lesions (\u0026le;\u0026thinsp;1cm) by 30% \u003csup\u003e[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. In bladder cancer, [\u003csup\u003e18\u003c/sup\u003eF]FDG causes high radioactivity within the bladder due to urinary excretion, making tumor indistinguishable from urine, whereas FAPI is excreted via the kidneys but does not concentrate in the bladder, achieving a detection sensitivity of 100% for primary tumors \u003csup\u003e[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003e.Additionally, FAPI uptake in salivary glands (SUVmean\u0026thinsp;=\u0026thinsp;2.57) and the gastrointestinal tract (e.g., colon SUVmean\u0026thinsp;=\u0026thinsp;1.8) is lower than that of [\u003csup\u003e18\u003c/sup\u003eF]FDG, reducing false negatives in the diagnosis of head and neck and abdominal tumors \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe advantage of FAPI in abdominal lesions stems primarily from its low physiological uptake and rapid clearance characteristics, which significantly improve lesion detection rates. In pancreatic cancer assessment, FAPI resolves the issue of lesion blurring caused by physiological pancreatic uptake and adjacent intestinal concentration seen with [\u003csup\u003e18\u003c/sup\u003eF]FDG.A meta-analysis showed that FAPI sensitivity for detecting primary pancreatic lesions reached 100%, higher than the 88.9% of \u003csup\u003e18\u003c/sup\u003eF-FDG (MD\u0026thinsp;=\u0026thinsp;7.51, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]\u003c/sup\u003e.In liver metastases, the low hepatic background of FAPI (SUVmean\u0026thinsp;=\u0026thinsp;1.5) resulted in a TBR of 4.4 for colorectal liver metastases, significantly higher than the 1.8 of [\u003csup\u003e18\u003c/sup\u003eF]FDG (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.042) \u003csup\u003e[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e.The low-background characteristic of FAPI comprehensively improves diagnostic accuracy by enhancing lesion contrast and reducing false positives.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section3\"\u003e \u003ch2\u003e3.3.2. Discussion on the \"Flip-flop Phenomenon\u003c/h2\u003e \u003cp\u003eAs immune organs, the physiological structure of lymph nodes and the dynamic changes in cellular composition (such as lymphocytes, macrophages, CAFs) under pathological conditions directly affect the distribution and signal characteristics of FDG and FAPI, resulting in the \"flip-flop phenomenon\"\u0026mdash;where the uptake patterns of FDG and FAPI in benign versus malignant lymph nodes may be opposite or complementary \u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e.Anatomically, lymph nodes consist of a capsule and internal parenchyma.The capsule is dense connective tissue that extends into the parenchyma to form trabeculae, constituting the scaffold of the lymph node.The parenchyma is divided into the peripheral cortex and the central medulla \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e.The stromal cell network of lymph nodes, particularly fibroblastic reticular cells (FRCs), constitutes a crucial 3D scaffold. As key stromal cells maintaining lymph node structure, FRCs typically exhibit low metabolic activity and FAP expression levels under steady-state conditions.Consequently, normal non-enlarged lymph nodes usually show mild or no \u003csup\u003e18\u003c/sup\u003eF-FDG uptake (SUVmax typically below 2.5), while FAPI uptake is even lower or close to background levels \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]\u003c/sup\u003e.When lymph nodes encounter antigenic stimulation (e.g., infection, tumor antigens), reactive hyperplastic lymph nodes show significantly increased \u003csup\u003e18\u003c/sup\u003eF-FDG uptake, often exhibiting a diffuse, symmetrical distribution, which is a major source of false positives \u003csup\u003e[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e.Studies show that in chronic inflammation or autoimmune diseases (e.g., rheumatoid arthritis, sarcoidosis, systemic sclerosis), involved lymph nodes can present with diffuse high FDG uptake, forming the basis for FDG positivity in the so-called \"flip-flop phenomenon\" \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e.In metastatic lymph nodes, in addition to the stromal reaction induced by tumor cells themselves (inducing host fibroblast conversion to CAFs), CAFs infiltrating the metastatic foci also abundantly express FAP.FAP expression levels become key to distinguishing benign from malignant lymph nodes: reactive hyperplasia (acute inflammation) typically has low FAP expression, while metastatic lymph nodes (especially epithelial tumor metastases) have high FAP expression due to CAF richness \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]\u003c/sup\u003e. Therefore, the \"flip-flop phenomenon\" in lymph node assessment implies that under specific pathological conditions, \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT and FAPI PET/CT may present opposite or complementary signal patterns for determining the benign or malignant nature of the same lymph node.\u003c/p\u003e \u003cp\u003eThe application of FDG-PET in IgG4-RD has been widely confirmed for its value in assessing disease activity and organ involvement, particularly in lymph node involvement. Research indicates that lymph nodes in IgG4-RD patients often exhibit high FDG uptake, with standardized uptake values (SUVmax) significantly higher than normal tissue, averaging between 4.0 and 7.0, reflecting a state of local metabolic activity \u003csup\u003e[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e.This high uptake characteristic correlates with the inflammatory nature of the disease; as a glucose analog, FDG accumulates in activated immune cells (such as lymphocytes and plasma cells), highlighting the lymphoplasmacytic infiltration characteristic of IgG4-RD lymph nodes \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e.Clinical case studies have further confirmed the practical application value of FDG-PET regarding the high uptake characteristics in IgG4-RD lymph nodes.A retrospective multicenter study including 21 IgG4-RD patients found that all patients showed abnormal lymph node FDG uptake at diagnosis or relapse, especially in mediastinal and hilar regions, and FDG-PET sensitivity (\u0026gt;\u0026thinsp;90%) exceeded that of conventional imaging like CT or MRI, with significant advantages in detecting small or asymptomatic lesions \u003csup\u003e[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e.In a case study by Taniguchi et al. \u003csup\u003e[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/sup\u003e, a 74-year-old patient showed increased FDG uptake in the spleen and lymph nodes (SUVmax\u0026thinsp;\u0026gt;\u0026thinsp;6) on FDG-PET, which was confirmed by biopsy as IgG4-RD-related splenopathy and lymphadenitis.In IgG4-RD, FAPI-PET is used to assess the degree of fibrosis because the disease is characterized by storiform fibrosis and theoretically should show high uptake; however, in practice, it presents a phenomenon of low lymph node uptake.In terms of technical parameters, the SUVmax of FAPI-PET in lymph nodes is lower than that of FDG, reflecting the heterogeneity of FAP expression \u003csup\u003e[\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]\u003c/sup\u003e.Lymph nodes are dominated by lymphoid follicular hyperplasia rather than significant storiform fibrosis, resulting in an insufficient number of FAP-positive fibroblasts. A prospective study by Luo et al. \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e clearly indicated that while involved lymph nodes showed high FDG uptake, there was no FAPI accumulation, supporting the hypothesis of a low degree of fibrosis.Secondly, disease subtype differences affect FAP expression: IgG4-RD can be classified into proliferative and fibrotic types, with the proliferative type dominated by inflammatory cell infiltration and the fibrotic type by fibrosis; research shows that FAPI uptake in the fibrotic subtype is significantly lower than in the proliferative type (SUVmax 10.93 vs. 17.67, P\u0026thinsp;=\u0026thinsp;0.005), and lymph nodes may more commonly belong to the proliferative or mixed type, leading to attenuated FAPI signals \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e.Furthermore, microenvironmental factors such as cytokine profiles may inhibit fibroblast activation.Early lymph node disease is dominated by inflammation, and FAPI uptake may enhance after fibrosis progression in later stages, but most studies focus on active-phase cases, underestimating late-stage changes \u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis hypothesis regarding the \"separation of inflammation and fibrosis\" was directly validated pathologically in the study by Schmidkonz et al. \u003csup\u003e[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]\u003c/sup\u003e.The study confirmed via immunofluorescence analysis of IgG4-RD patient tissues that \u003csup\u003e18\u003c/sup\u003eF-FDG uptake is highly correlated with the infiltration density of CD45\u0026thinsp;+\u0026thinsp;lymphoplasmacytes (representing inflammatory activity), whereas \u003csup\u003e68\u003c/sup\u003eGa-FAPI uptake specifically corresponds to the abundance of FAP+/Vimentin+ activated fibroblasts (representing fibrotic burden).More importantly, this difference in pathological mechanisms directly leads to the \"divergent\" performance of the two in treatment monitoring.After anti-inflammatory therapy (e.g., rituximab), although inflammation-dominant lesions showed a significant decrease in FDG uptake, FAPI signals persisted in some lesions, revealing residual fibrotic activity after pure anti-inflammatory treatment.This finding not only explains the aforementioned imaging discrepancies but also establishes a biological foundation for the application of FAPI in clinical efficacy monitoring.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section3\"\u003e \u003ch2\u003e3.3.3. Clinical Translational Significance of FAPI PET in IgG4-RD\u003c/h2\u003e \u003cp\u003eThe emergence of FAPI PET brings a revolutionary tool for the precise diagnosis and comprehensive assessment of IgG4-RD.By targeting activated fibroblasts\u0026mdash;the key effector cells in the fibrosis process\u0026mdash;it overcomes the inherent limitations of traditional imaging modalities, significantly improving the accuracy of disease detection and staging. Although \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT is commonly used to assess IgG4-RD, limited by its dependence on glucose metabolism, it often suffers from insufficient lesion detection sensitivity and contrast due to high physiological uptake in organs masking lesions or overlapping uptake between lesions and inflammation/tumors \u003csup\u003e[\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]\u003c/sup\u003e.FAPI PET fundamentally alters this predicament. Its target, FAP, is highly expressed in activated fibroblasts \u003csup\u003e[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e. This characteristic endows FAPI PET with extremely low physiological background signals system-wide, thereby achieving superior target-to-background contrast.Studies indicate that FAPI PET can discover additional involved organs that FDG PET/CT or other conventional imaging modalities failed to detect.A typical case is the detection of lacrimal gland involvement by FAPI PET that was not shown by FDG, which directly influenced the patient's clinical staging and treatment decision \u003csup\u003e[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]\u003c/sup\u003e.Furthermore, a study based on [\u003csup\u003e18\u003c/sup\u003eF]AlF-NOTA-FAPI-04 PET/CT found that in up to 50% of IgG4-RD patients, the number of involved organs detected by PET/CT exceeded the sum of those found by physical examination, ultrasound, and CT \u003csup\u003e[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e.Moreover, FAPI PET helps distinguish disease subtypes, preventing misjudgment of disease activity.The study by Liu et al. \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e classified IgG4-RD into two subtypes: proliferative and fibrotic.The proliferative type is characterized primarily by inflammatory cell infiltration, while the fibrotic type is characterized by significant fibrosis.These two subtypes differ distinctly in their response to treatment and prognosis.FDG PET uptake may be similar in these two subtypes, making them difficult to distinguish.However, FAPI PET can effectively differentiate between the two.It was found that FAPI uptake in lesions of proliferative subtype patients (SUVmax: 17.67\u0026thinsp;\u0026plusmn;\u0026thinsp;7.46) was significantly higher than in the fibrotic subtype (SUVmax: 10.93\u0026thinsp;\u0026plusmn;\u0026thinsp;2.22, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.005), and their target-to-background ratio (TBR) was also higher (15.49\u0026thinsp;\u0026plusmn;\u0026thinsp;8.23 vs. 9.25\u0026thinsp;\u0026plusmn;\u0026thinsp;3.00, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015) \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e.More importantly, the \"PET index\" (FAPI SUVmean / FDG SUVmean) proposed by the researchers was significantly higher in the proliferative subtype compared to the fibrotic type (1.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.41 vs. 1.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.39, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.039) \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e.This index can quantify the weight of fibroinflammatory activity, directly reflecting disease activity. For fibrotic patients, relying solely on FDG PET might lead to a misjudgment of stable disease due to low metabolism, while active fibrosis is actually progressing silently.\u003c/p\u003e \u003cp\u003eChanges in FAPI PET uptake before and after treatment can serve as direct imaging biomarkers for fibrosis reversal or progression.A preclinical study monitoring pulmonary fibrosis treatment using FAPI PET provided strong evidence for this concept.In that study, untreated mouse models of pulmonary fibrosis showed [\u003csup\u003e68\u003c/sup\u003eGa]FAPI uptake peaking at 21 days, whereas after treatment with the anti-fibrotic drug pirfenidone, FAPI uptake in the mouse lungs significantly decreased, consistent with a reduction in histologically measured fibrotic area \u003csup\u003e[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]\u003c/sup\u003e.This model clearly demonstrates that FAPI PET can track the response of fibrosis to treatment in real-time and with accuracy.Applying this principle to IgG4-RD, we can perform periodic FAPI PET examinations during treatment to determine the effectiveness of anti-fibrotic therapy by quantitatively analyzing changes in lesion SUVmax, TBR, or total load (e.g., TL-FAPI).A sustained reduction in FAPI uptake predicts the regression of fibrotic components, which is crucial for assessing long-term prognosis and organ function recovery.Furthermore, combined with the PET index (\u0026gt;\u0026thinsp;1.5 indicating high recurrence risk) proposed by Liu et al. \u003csup\u003e[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]\u003c/sup\u003e, FAPI can serve not only to monitor current fibrotic activity but also as a prognostic biomarker to guide the development of long-term maintenance therapy strategies.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Limitations\u003c/h2\u003e \u003cp\u003e This study has certain limitations.First, due to the low incidence of IgG4-RD and the fact that FAPI imaging technology is still in the clinical dissemination phase, the number of head-to-head comparative studies meeting inclusion criteria was limited (only 3), with a small overall sample size (n\u0026thinsp;=\u0026thinsp;90).This limited the statistical power to conduct more in-depth subgroup analyses (e.g., different organ subgroups or different fibrosis stages).Second, significant heterogeneity existed among the included studies; some were of retrospective design, which may introduce selection bias.Additionally, although all patients had a definitive diagnosis, it was practically difficult to histopathologically verify every PET/CT-positive lesion; the characterization of some small lesions relied on clinical follow-up, which may introduce some bias in the assessment of diagnostic efficacy.Finally, this study mainly focused on a cross-sectional comparison of diagnostic efficacy and lacked longitudinal data regarding FAPI in monitoring treatment response and long-term prognostic assessment, which still requires further verification by future large-sample, multicenter prospective studies.\u003c/p\u003e \u003c/div\u003e "},{"header":"4. Conclusion","content":"\u003cdiv id=\"Sec23\" class=\"Section2\"\u003e \u003cp\u003eIn summary, this systematic review and pooled analysis demonstrates that \u003csup\u003e68\u003c/sup\u003eGa-FAPI PET/CT possesses unique clinical value in the diagnosis and assessment of IgG4-related disease (IgG4-RD).Benefiting from its specific targeting mechanism for fibroblast activation protein (FAP) and extremely low abdominal physiological background uptake, \u003csup\u003e68\u003c/sup\u003eGa-FAPI exhibits sensitivity and image contrast significantly superior to traditional \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT in detecting parenchymal organ involvement, such as in the pancreas, bile ducts, and salivary glands.However, in the assessment of lymph node lesions, \u003csup\u003e18\u003c/sup\u003eF-FDG retains an irreplaceable advantage.This finding suggests that the two tracers reflect different pathophysiological processes of IgG4-RD\u0026mdash;fibrotic activity and inflammatory cell infiltration, respectively\u0026mdash;indicating that they are not simple substitutes for each other but rather complementary in clinical application.\u003csup\u003e68\u003c/sup\u003eGa-FAPI holds promise as a powerful complementary imaging tool, particularly suitable for characterizing fibrosis-dominant lesions, detecting small occult lesions, and accurately staging the systemic extent of the disease.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003e• Ethics approval and consent to participate\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eAs this study is a systematic review and meta-analysis of publicly available data, it did not involve human or animal subjects. Therefore, ethical approval and informed consent were not required.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e• Consent for publication\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eNot applicable. This study did not involve individual patient data or images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e• Availability of data and material\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eAll data used in this study were extracted from publicly available peer-reviewed articles indexed in PubMed, Embase, and Web of Science. The original data supporting the pooled analysis are available within the article and its supplementary materials. Raw data from individual studies can be accessed through the respective publications.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e• Competing interests\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e• Funding\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eThis work was supported by the Guiding Scientific Research Project of Shiyan Science and Technology Bureau (Grant No. 25Y158).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e• Authors' contributions\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eZJ (corresponding author) conceptualized the study, performed the literature search.HQF is responsible for drafting the initial version of the article. CX is responsible for the production, acquisition, and analysis of images.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e• Acknowledgements\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003eNot applicable. The authors wish to thank the investigators whose studies contributed to this analysis.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eInoue D, Yoshida K, Yoneda N, et al. IgG4-related disease: dataset of 235 consecutive patients. Medicine. 2015;94(15):e680. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/MD.0000000000000680\u003c/span\u003e\u003cspan address=\"10.1097/MD.0000000000000680\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAdam Z, Zeman D, Čerm\u0026aacute;k A, et al. [IgG4-related disease. Clinical manifestation differential diagnosis and recent International Diagnostic Criteria for IgG4-related disease]. 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Pharmaceuticals (Basel). 2024; 17 (6): \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3390/ph17060726\u003c/span\u003e\u003cspan address=\"10.3390/ph17060726\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejre","sideBox":"Learn more about [EJNMMI Research](http://ejnmmires.springeropen.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejre/default.aspx","title":"EJNMMI Research","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"IgG4-related disease, 68Ga-FAPI, 18F-FDG, PET/CT, head-to-head comparison, fibrosis, PET index","lastPublishedDoi":"10.21203/rs.3.rs-8932863/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8932863/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003e1.1. Background\u003c/h2\u003e \u003cp\u003eIgG4-related disease (IgG4-RD) lacks standardized imaging criteria. This study systematically reviewed head-to-head comparisons of \u003csup\u003e68\u003c/sup\u003eGa-FAPI and \u003csup\u003e18\u003c/sup\u003eF-FDG PET/CT to clarify their complementary roles in diagnosing and staging IgG4-RD.\u003c/p\u003e\u003ch2\u003e1.2. Main body\u003c/h2\u003e \u003cp\u003eThree high-quality studies (n\u0026thinsp;=\u0026thinsp;90) were pooled. \u003csup\u003e68\u003c/sup\u003eGa-FAPI showed significantly higher SUVmax and target-to-background ratios (TBR) in parenchymal organs (pancreas, salivary glands) vs \u003csup\u003e18\u003c/sup\u003eF-FDG (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), offering superior lesion contrast. While \u003csup\u003e18\u003c/sup\u003eF-FDG detected more lymph node activity, \u003csup\u003e68\u003c/sup\u003eGa-FAPI identified 136 vs 78 total lesions, improving systemic burden assessment. Pathology correlated FAPI with fibrosis and FDG with inflammation, defining a \"flip-flop\" pattern. A FAPI/FDG ratio\u0026thinsp;\u0026ge;\u0026thinsp;1.5 predicted relapse risk.\u003c/p\u003e\u003ch2\u003e1.3. Conclusion\u003c/h2\u003e \u003cp\u003e \u003csup\u003e68\u003c/sup\u003eGa-FAPI excels in parenchymal organ involvement, while FDG highlights inflammatory lymphadenopathy. Combining both tracers enables multimodal evaluation of fibroinflammatory activity, guiding personalized management and prognostication in IgG4-RD.\u003c/p\u003e","manuscriptTitle":"Complementary Roles of 68Ga-FAPI and 18F-FDG PET/CT in Evaluating IgG4-Related Disease: A Systematic Review and Pooled Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-08 16:37:23","doi":"10.21203/rs.3.rs-8932863/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2026-04-12T10:07:20+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-03-01T07:24:04+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-27T16:08:28+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-27T08:29:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"EJNMMI Research","date":"2026-02-26T21:27:08+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"ejnmmi-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejre","sideBox":"Learn more about [EJNMMI Research](http://ejnmmires.springeropen.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ejre/default.aspx","title":"EJNMMI Research","twitterHandle":"@officialEANM","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"9ff7d7c9-160e-496b-82ab-642350b50b19","owner":[],"postedDate":"March 8th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-08T08:43:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-08 16:37:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8932863","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8932863","identity":"rs-8932863","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}