Fluorescence optical imaging for treatment monitoring in patients with early and active rheumatoid arthritis in a 1-year follow-up period

To monitor therapeutic response in patients with rheumatoid arthritis (RA), clinical disease activity scores such as DAS28 are applied [1]. Besides, more sensitive and objective imaging modalities are recommended in the clinical management of RA [2]. Magnetic resonance imaging (MRI) and musculoskeletal ultrasound (US) are both widely used in clinical practice and research within the field of RA [3‐8]. MRI-detected pathologies such as synovitis and tenosynovitis are highly responsive to antirheumatic treatment [9‐11]. However, MRI has the disadvantage of high costs, time exposure, and occasional contraindications (e.g., pacemaker and claustrophobia) [12]. In several studies, US-detected synovitis and tenosynovitis have also been shown to be sensitive to change under therapy, especially in Power Doppler mode (PDUS) [13‐16] reflecting disease activity. US is a cost-effective, widespread method that is risk-free for patients, is indefinitely repeatable, and involves less inconvenience than MRI. Drawbacks may be the dependency on the examiner [17] and the inability to pairwise compare baseline and follow-up images immediately while investigating unless all images are saved for analysis later on; however, US images are usually saved as “still images” (lost of dynamic approach).

In search of an imaging method for the optimal detection of disease activity, new procedures are developed and investigated. Since 2009, the fluorescence optical imaging (FOI) “Xiralite” (Xiralite GmbH, Berlin, Germany) has been shown to detect inflammation in preclinical studies [18, 19] as well as in humans [20‐26] in the joint regions of both hands. The basis of the Xiralite method is the demonstration of an impaired microcirculation caused by the inflammatory process of arthritis. Here, the enhancement of an intravenously applied dye indocyanine green (ICG) is evaluated. FOI is a non-ionizing technique that examines both hands in one session of 6 min. Besides, the examination itself can be performed by clinical assistants. Impediments in the sense of resulting contraindications are an impaired liver function, since the applied dye is primarily excreted biliarily [27]. Furthermore, an allergic reaction to the ICG solution can occur [28]. However, the overall risk of ICG to the patient is low [29].

Previous studies have demonstrated good agreements between FOI, clinical assessment, MRI, and US [21] as well as a moderate und substantial reliability for the scoring of FOI images [22]. Additionally, FOI may also detect subclinical inflammation [25]. Only one study has evaluated the responsiveness of FOI, so far. Meier et al. found a reduction in the signal intensity during therapy response in a group of patients with forms of different arthritis who were examined by a computer-based evaluation of FOI and MRI; however, the observed group was heterogeneous and only investigated over a time period of 6 months [30].

The aim of the present study was the investigation of FOI’s ability to reflect treatment response in a homogenous cohort of patients with early and active RA over a period of 12 months. Besides, we aimed for exploration of its correlations with clinical outcomes such as DAS28. The correlation with US as a common imaging modality in daily rheumatological practice was set as a secondary outcome.

This study is a subproject (No. 7) of the Arthromark project as a national research network in Germany funded by the Federal Ministry of Education and Research (BMBF). The main goal of the several Arthromark subprojects is the identification of new biomarkers including the application and assessment of new and modern imaging techniques in terms of making a diagnosis and follow-up examinations in patients with RA, psoriasis arthritis, and spondyloarthritis [31].

In this subproject, we included 42 patients with early (disease duration < 24 months) and active (DAS28 > 3.2) RA, who started therapy with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or escalated therapy with initiation of biologic therapy (bDMARD) after failure of conventional therapy. Over a period of 1 year, patients were examined clinically and by US (for further description of additional US, see Additional file 1) five times (baseline, after 6 weeks, and 3, 6, and 12 months). FOI was performed at baseline and after 12 months in 35 patients who were included in these analyses (in seven patients, the 12-month visit was not performed).

Patients’ characteristics are presented in Table 1. Our analyses focused on the 35 of 42 patients who completed the study after 12 months.

To our knowledge, this present study is the first one describing the changes of FOI in a homogeneous cohort of patients with early and active RA over a period of 12 months under antirheumatic therapy.

Concerning FOI, we found significant reductions in the FOI sum score in phase 1 in the total cohort, whereas the other phases remained stable. These results are in line with previous results by Meier et al., who found a significant reduction in early signal intensity after 24 weeks of therapy using a computer-based evaluation of FOI [30]. In a study by Werner et al., phase 1 featured the highest agreement between clinical examination and FOI. In addition, the highest specificity was calculated for phase 1 compared to MRI and US in this study [21], which was also confirmed by Krohn et al. [24]. Besides, phase 1 did not show any pathological changes in a healthy cohort, confirming the hypothesis that this early phase reflects active inflammation with increased vascularization and therefore high clinical disease activity [21]. In a previous study, we examined FOI in patients with either osteoarthritis (OA) or RA. OA patients showed significantly less activity in phase 1 (maximum degree 1), but a consistently high signal accumulation in phase 2 (especially in the wrist) [26]. These results support the hypothesis that phase 1 detects an active inflammation [21, 22] since OA is usually characterized by a less pronounced inflammation as compared to systemic inflammatory joint diseases.

In our analysis, we did not find a significant correlation between the change of phase 1 and joint count. The lack of correlations between phase 1 and clinical parameters may be due to different parameters we assess in clinical examination and FOI. While we investigate a disturbed microcirculation in FOI, we document morphological changes in swollen fingers as a result of infiltrated cells in the synovial membrane and pannus. The impaired microcirculation visualized by FOI comprises neoangiogenesis, hyperperfusion, and capillary leakage within the inflammatory process of RA [36]. It may be assumed that both pathologies (microcirculation and morphological changes) within the articular region appear on different time points in the disease course. On the other hand, neoangiogenesis is an important component in the formation of pannus and, therefore, not only found around the inflamed joint [36]. Another explanation for the lack of correlation may be false-positive findings of FOI. However, Werner et al. demonstrated a low rate of false-positive findings between 0.5 and 5% by FOI [22]. Thus, our results stand in contrast to the results by Werner et al. who presented good agreement rates and low, but significant, correlations between FOI and clinical examination. It should be noted that FOI detects any inflammation including scratches, plaques, and insect bites. On this account, the evaluation requires a well-trained investigator [22]. However, the localization, form, and temporal distribution of enhancement in the individual FOI phases allow a differentiation [22] and may indicate the underlying pathology or possible disease [26].

In addition, Werner et al. suggested divergence between local inflammation in the hand and systemic inflammation [21]. Furthermore, high variance for components of the DAS28 was recently described [37], while FOI is a more objective technical tool.

After 1 year under csDMARD or bDMARD therapy, approximately 46% of the patients in our study achieved a clinical response stage according to the EULAR response criteria [32‐34] and showed a reduction in disease activity according to the treat-to-target principle (T2T). The change in FOI sum scores was similar in patients with and without a clinical response. The significant reductions in phase 1 also in non-responders probably show a more objective reduction of inflammation by FOI, while the clinical non-response can also depend on individual person-related (i.e., psychological) factors which may lead to elevated global disease activity on VAS. Recently, Hammer et al. showed no association between tender joints and synovitis in GSUS and PDUS, while a strong correlation between swollen joints and US synovitis was calculated. In addition, they found a primary associationn between tender joints and patient-reported joint pain [38]. These findings support that the parameters of DAS28 hardly correlated with the sum scores of FOI also in this present study. Similar results for FOI were published by Werner et al. assuming different characteristics of pathologies [21].

We conducted correlation analyses between musculoskeletal ultrasound and FOI findings. At baseline examination, strong correlations were found between all FOI phases and the ultrasound parameters, especially tenosynovitis in PDUS. The strongest correlations were found for FOI phase 2 at both baseline and after 12 months of therapy. In contrast, phase 1 did only show a positive correlation with synovitis in GSUS after 12 months follow-up. The meaning of phase 2 as a marker of subclinical activity has already been discussed in previous studies [21, 22, 24]; however, no longitudinal data exist yet showing a predictive value of phase 2, for example in terms of erosive disease or flare prediction. The strong signal accumulation could be caused by increased vascularization due to chronic inflammation. The low correlations of phase 1 with US at month 12 may indicate that there was no or only a small amount of acute inflammation after 1 year of intensive therapy, whereas the greyscale US synovitis findings can persist. FOI phase 1 is probably a reflection of acute inflammation. A good response of early enhancement in FOI to therapeutic interventions demonstrated by Meier et al. showed a decrease of early signal intensity after 6 months in response to therapy [30].

In conclusion, activity in FOI phase 1 changed significantly over 1 year under therapy in the group of responders regarding the parameter of clinical remission (DAS28). However, a significant change of FOI phase 1 was also observed in non-responders, so we cannot objectively deduce a therapy response of phase 1. However, the correlation of FOI with ultrasound as a validated and well-established imaging technique in daily rheumatological practice should be emphasized. In the issue, the role of FOI in therapy monitoring needs to be investigated in further studies.