Our data shows that ICG enhanced optical imaging can detect inflamed joints. The relatively high dose of ICG used provided a contrast effect that lasted for almost half an hour. Fusion of OI and X-ray images leads to an improved anatomical localization of the inflammatory process.
Different approaches have been described for the evaluation of arthritis with optical imaging. Imaging of laser light scattering without any contrast agent can detect inflammation of the PIP joint with a sensitivity of 80% and a specificity of 89% (5
) However, analysis of these data requires the use of non trivial algorithms and changes between normal and inflamed joints were not evident on qualitative imaging. The addition of fluorescent contrast agents has the potential to improve both sensitivity and specificity of optical imaging (4
). The fluorescent probe can either be injected intravenously and depict the hypervascularity of inflamed joints or the fluorescent probe can be used to label leukocytes and depict the accumulation of these cells in inflamed joints, similar to radiotracer-based leukocyte scans (10
For the scope of RA diagnosis and monitoring, direct injections of fluorescent probes followed by optical imaging appear to be most practical (4
). Several investigators developed cell specific fluorescent dyes in order to optimize the specificity of the optical imaging approach. Chen et al developed a fluorescent contrast agent bound to folate that was preferentially taken up by activated macrophages in arthritic joints of experimental animals. The amount of detected activated macrophages correlated with articular destruction and poor disease prognosis (11
). Unfortunately, such specialized dyes are not FDA approved and therefore have limited clinical applicability. FDA approved contrast agents would facilitate clinical translation. A recent study by Fischer et al (6
) showed the feasibility of ICG for arthritis imaging in a Lyme arthritis based mouse model. Following injection of ICG at a dose of 1-2 μmol/kg a relatively short lived signal enhancement of inflamed joints was noted at 60-120 seconds post injection. For imaging of multiple joints, a lengthier enhancement would be preferred.
ICG has been used extensively for over four decades in the fields of ophthalmology for retinal imaging and cardiology for detection of cardiac output. ICG has a well documented safety profile (12
). It may very rarely (<1/10.000) cause anaphylactoid and anaphylactic effects such as hyperthermia, nausea, pruritus, urticaria, tachycardia, hypotension, dyspnea and bronchospasm (12
). We used a higher dose for rodents as described for patients in order to compensate for the shorter blood half life of ICG in rodents (1.5 - 2.3 min) as opposed to patients (3 - 4 min) (6
). The relatively high ICG dose provided a prolonged contrast enhancement and allowed for sequential imaging of multiple joints without additional contrast injection.
Several translational optical imaging devices have been recently introduced to the clinics, such as optical mammography (custom device, Taroni et al) (13
) and optical arthritis scanners (Xiralite, Mivenion Ltd, Germany) (14
). A custom built ICG enhanced OI device for hand imaging has recently been shown by Fischer et al to correlate well to enhanced MRI in detection of rheumatoid arthritis in patients (15
We acknowledge various limitations of our study. Our study protocol includes the acquisition of multiple X-rays since standardized positioning of the animals in the scanner for all time points was not possible. In a clinical setting, however, where a patient's hands and feet are imaged in a standardized position only one X-ray per examination would be required.
Furthermore OI does not require ionizing radiation whereas the combination with X-ray does. However, nearly every patient with RA will receive an initial X-ray and the addition of this imaging modality compensates for the lack of anatomical information in OI. Thus, the combination of both modalities would not increase radiation exposure for patients; it will, however, improve the sensitivity of the diagnostic test and the sensitivity of follow-up exams that monitor disease burden and progression. While X-rays might not be required to localize optical enhancement to the investigated knee and ankle joints of rats, X-rays will be helpful to localize areas of enhancement to more complex structures such as a hand of a patient.
We also acknowledge the limitations of our animal model of acute arthritis which is self-limited and resolves spontaneously within 4-5 days. Future studies will need to assess the value of our diagnostic approach for the detection of early stages of arthritis and for long term therapy monitoring, as this would be more pertinent to patient applications.
In summary, we have shown that the FDA-approved ICG can be used to detect joint inflammation in an animal model of arthritis. The short examination time coupled with the patient-friendly imaging modality could easily allow for detection of early inflammatory changes in rheumatoid arthritis and facilitate therapy monitoring.