ICG-enhanced FOI with the Xiralite® system is a novel imaging technique that has been shown to visualize inflammation in arthritis of wrist and finger joints and has been evaluated in various validation studies in adult rheumatology [
22‐
24,
31,
32]. The aim of this study was to acquire data regarding the use of FOI in children and adolescents with joint diseases by comparing it to findings in both sonographic and CE.
Patients with juvenile idiopathic arthritis
Consistent with previous studies in adults [
22‐
24], FOI showed a higher rate of positive findings than the other compared modalities. Most signals were found in P2, which was also the most sensitive phase compared to CE (62.6%). This supports the hypothesis that it might be the most valuable phase for detecting subclinical activity [
22‐
24]. However, there is a need for further evaluation to prove this.
Agreement of FOI and CE was comparable to agreement of GSUS/PDUS and CE, whereas FOI overall sensitivity for detecting clinically active arthritis was higher than GSUS/PDUS sensitivity (75.2% vs 57.3%/32.5%).
Agreement of FOI and US was good, especially agreement with PDUS (up to 81.9%), which reflects the fact that both FOI and PDUS display acute inflammatory changes rather than chronic changes. Sensitivity of FOI compared to US was moderate. The highest values were reached if increased signal intensities in any phase were considered (GSUS 67.3%, PDUS 72.0%). Analyzing the phases separately, highest sensitivity was found for FOI P1 compared to hyperperfusion in PDUS in JIA patients with clinically active arthritis (59.8%) with corresponding high specificity (74.0%). This supports the theory by Werner et al
. [
22] that P1 reflects high synovial vascularization and thus correlates best with disease activity [
33]. However, these results distinguish from results of previous studies comparing FOI to US which found P2 to be the most sensitive phase [
22‐
24].
In accordance with adult studies, highest specificity compared to both GSUS and PDUS was found for P3 (94.3% and 91.7%). This was the phase showing least signal intensity increase; presumably it reflects increased capillary permeability with abnormal persistency of ICG and is therefore mostly found positive in osteoarthritis [
22,
23,
34].
Differences in the characteristics of the FOI phases compared to previous studies might result from the higher variation of ICG distribution patterns we observed in children and adolescents compared to adults. Defining the phases according to the standardized protocol was difficult in several cases, where the ICG distribution deviated from the known characteristic flow behavior. This is possibly due to growth-related vascular changes and might have had an influence on sensitivity and agreement rates of the individual phases. Therefore, the current standard of interpretation in adult rheumatology by Werner et al. [
22,
23]—in particular the definitions of the phases—might have to be reevaluated for pediatric rheumatology. This could also be concluded by means of the moderate correlations of US and FOI scores on the joint and patient levels (Tables
3 and
4). We found no relevant differences in the distribution of FOIAS scores between patients aged < 13 years and patients aged ≥ 13 years (see Fig.
4). Nevertheless, further age-related examinations are needed for evaluation of growth-related changes in FOI.
Both FOI and US detected a high number of positive results in clinically asymptomatic joints of JIA patients. In adult rheumatology, it is known that residual synovitis in patients with rheumatoid arthritis in clinical remission is frequent and predicts the risk of relapse and ongoing structural joint damage [
35]. Even though there are follow-up reports suggesting that subclinical arthritis detected by US also predicts development of clinical arthritis in JIA patients [
36], direct evidence from comparing US to histopathological findings—as has been provided for adults—has not been (and most likely will not be) tested for children. Pre/post comparisons of adult patients with inflammatory arthritis in clinical remission suggested that positive signals in FOI in clinically asymptomatic joints may also predict a relapse after premature withdrawal of treatment [
37]. A recent study found FOI to be particularly sensitive in detecting clinically silent inflammation in joints that were positive by US [
31].
In our study, agreement of US and FOI in clinically inactive joints that presented abnormalities in imaging was relatively low (up to 25.4%), showing that such preclinical/subclinical findings in children and adolescents have to be interpreted with caution. After all, validity of US in pediatric rheumatology has still not been fully established and preliminary standardized definitions of synovitis in US were established only recently [
38]. Additionally, it is known that there is a wide range of growth-related variations in joints of children and adolescents that can be seen on imaging. In MRI studies of patients with JIA, changes in bone shape, signal intensity, and the amount of joint fluid were found that were partly unrelated to disease activity [
39]. Moreover, bony depressions resembling erosions are frequently seen on MRI of healthy children [
19]. Therefore, the clinical importance of such findings in both MRI and FOI remains to be determined and it is unclear whether FOI findings in asymptomatic joints of JIA patients demonstrate subclinical inflammation and thus predict development of clinically apparent arthritis. In the future, follow-up studies could help in evaluating their significance.
Patients with arthralgia without any known inflammatory rheumatic disease
This group served as a control group, because none of the patients presented clinical signs of an inflammatory joint disease. Previous examinations of healthy controls and individuals with arthralgia without any sign of inflammatory rheumatic disease showed a low rate of positive findings in FOI (0–5%) [
22,
23]. However, a vast majority of 91% of this group had increased signal enhancements in at least one joint and phase. Also, 74% of the patients showed abnormalities in US suggestive of synovitis.
Remarkably, there was only moderate agreement between the positive results detected by US and FOI, suggesting that the mechanisms causing such findings differ between the two techniques. This is most likely due to the fact that FOI is based on different physical principles than US, such as light optics and microangiography. Thus, it should be considered a complementary rather than a competitive imaging method.
The high number of positive signals in both US and FOI resulted from many joints being scored grade 1. Excluding those joints greatly minimized positive results and led to high specificities (FOI 94.5–99.2%, US 97.4%). For clinical use, this could mean that FOI tends to overestimate findings and that discreet findings with scores < 2, especially in P2, should be interpreted with caution in children with suspected inflammatory rheumatic diseases, as they might not be a sign of active arthritis but of mechanical stress or blood flow alterations. As discussed before, this possibility should also be considered for patients with inflammatory diseases with positive signals in clinically inactive joints. However, any finding in P3 should be taken seriously, as this highly specific phase might reflect the presence of inflammation.
Most positive results in both US and FOI in patients with non-inflammatory diseases were found in the wrists. Interestingly, these results are compatible with observations in a healthy control group whose wrists were examined by MRI, where a high prevalence of increased volumes of joint fluid, signal changes similar to bone marrow edema, and bony depressions resembling erosions were found [
19]. Both MRI and FOI findings might reflect mechanical stress through the high use of this part of the hand during daily activity.
The predictive value for discrimination between active inflammatory and non-inflammatory conditions was calculated. We found it to be comparably high for both GSUS/PDUS and FOI (0.80/0.85 and 0.79) with slight advantages for US, showing that they are equally valid methods for differential diagnosis in children and adolescents with unclear joint pain.
Limitations
Our study has some limitations. Specific limitations of the technology include the lack of visualization of anatomic structures as well as the limited ability to assess palmar inflammation due to overlying structures reducing the depth of light penetration, most notably in the area of MCP joints. Also, FOI is currently available for examination of hands and wrists only, whereas the most common category of JIA—oligoarthritis—is often manifest in the knee or ankle joint. Therefore, the method might be more valuable for polyarticular-course JIA. Furthermore, it is limited to older children as the method’s fixed setup requires the patient’s capability to keep still for 6 minutes as well as a minimum arm’s length. The youngest patient examined in our study was 6.5 years old.
FOI demonstrates any inflammation of the hand region including scratches or psoriatic plaques, which can result in signal enhancement similar to synovitis. Even though experienced readers are able to identify signals caused by such skin lesions, any clinical findings should be documented in order to be considered in image interpretation [
40].
FOI is a procedure that includes an IV injection with potential side effects, like circulatory problems and allergic reactions. In our study, FOI examination was tolerated well, with one report of circulatory problems due to peripheral IV insertion before the fluorescent compound was applied.
The study population was rather inhomogeneous including several patients with unclear clinical findings at the time of examination. In hindsight, this limitation could be reduced by verifying every patient’s diagnosis approximately 1 year after the examination. Another limitation was the use of two different US machines with potential variance in resolution and display.
Ultimately, we were confronted with the problem that there is no assured gold standard for detection of synovitis in children, which is why sensitivities and specificities should be regarded with reserve. Because of the fact that MRI is an invasive technique and not a routine procedure in pediatric rheumatology, we were not able to include it as a reference method in our study.