This first in man real-world prospective study investigated the use of ex vivo OFDI for the diagnosis of GCA in the acute setting. In this study, OFDI was able to provide rapid imaging of TAB specimens with a diagnostic accuracy approaching that of histological examination.

A range of diagnostic techniques are used in acute GCA, but each has drawbacks and limitations. There is no single test that can be relied upon for the diagnosis of GCA and tests must be interpreted within the context of the clinical history, examination, and laboratory features including erythrocyte sedimentation rate, C-reactive protein, and platelet count. While TAB is still considered the gold standard, owing to its specificity of 100% [7], it has significant shortcomings [1]. The estimated sensitivity is 77% [3], due to a false negative rate of up to 44% [8] which likely stems either from the 1–2 cm biopsy specimen being within a ‘skip lesion’ – a part of the vessel that does not contain histopathological features of the disease, or from iatrogenic damage to the biopsy specimen [2]. Furthermore, the delay in histopathological examination and reporting may result in a period of potentially unnecessary high-dose corticosteroid treatment. TAB also carries a risk of surgical complications such as bleeding, infection and facial nerve injury [4] which may be greater than previously assumed [7]. Non-invasive methods of GCA diagnosis such as ultrasound, T1 weight contrast-enhanced MRI diagnosis and 18F-FDG PET/CT negate these risks but carry limitations of their own. Ultrasound achieves a sensitivity of 68–88% and a specificity of 77–96% [9,10,11], and although the specificity of ultrasound is greatly enhanced in the presence of a halo sign [12,13,14], only 63% of patients diagnosed with GCA on TAB have a halo sign on ultrasound [15]. Recent improvement in ultrasound technology and higher-resolution imaging have led to high inter-rater and intra-rater agreement with optimism for improved utility in future [16]. The modality still requires high levels of expertise and experience. Other less commonly utilised modalities include T1 weighted contrast-enhanced MRI with a sensitivity of 78–94% and specificity of 78–90% [17,18,19], and 18F-FDG PET/CT with a sensitivity of 64–92% and a specificity of 85–100% [20,21,22]. However, MRI is expensive, time consuming, and contraindicated in certain patients such as those with magnetic prostheses, while 18F-FDG PET/CT carries the long-term risks associated with low-level radiation exposure [23, 24], specifically an increased risk of genetic aberrations and neoplastic disease. Both modalities may be less widely available for immediate diagnostic purposes, particularly in smaller centres and during unsocial working hours.

OFDI has several important advantages over other diagnostic modalities. As a partially invasive investigation, in-vivo OFDI would likely present a lesser risk of procedural complications than TAB. The use of catheter angiography is well established within cardiology and carries less than a 1% risk of significant complications [25]. Owing to an image resolution (10–20 μm) that is far superior to any non-invasive diagnostic techniques, it has been shown that OFDI can detect cellular level changes such as FIEL and the presence of MNGCs. This may be particularly beneficial in defining early pathological change, or subtle diagnostic cellular pathology in patients on corticosteroids. Furthermore, with results that are rapidly available without the need for histological processing and evaluation, OFDI is less likely to delay diagnosis and the associated risks of high-dose corticosteroid treatment.

Intimal wall thickening is a useful and important clinical parameter that, as this study has shown, can be detected on OFDI, aiding the diagnosis of acute vasculitis. Although histological intimal wall thickness will vary over the specimen length due to ‘skip lesions’, it is considered an objective measurement and a defining feature of acute vasculitis. Marked histopathological thickening of the intima is strongly associated with increased inflammatory infiltrate [26] and the extent of intimal thickening seems to be predictive of the development of ischaemic neuropathy and ophthalmic symptoms [27]. Additionally, it has previously been shown that an increased intima-media thickness can be used to distinguish vasculitic from normal arteries in suspected GCA [28] and current evidence suggests that high-resolution imaging of intimal thickness is a robust measurement indicative of vasculitis that is minimally effected by corticosteroid use [29]. This study yielded a difference in MIT measured by OFDI and histology. This may derive from differences in preparation, with OFDI being conducted on specimens submerged in saline and histology on specimens prepared in formalin, but also from differences in precisely which section of the intima was being measured in the two methods. Moreover, the tissue penetration of the OFDI technology used in the present study allows for the measurement of a maximum wall thickness of approximately 0.4 mm. This is sufficient to confirm the presence of increased intimal thickness but cannot provide a precise value for the thickest intimas. Greater tissue penetration may be achievable with longer wavelength light, but this would be at the compromise of image resolution.

MNGCs are present in approximately 50% of temporal artery biopsies and within this context, are considered pathognomonic of GCA [30]. The diameter of MNGCs is highly variable but typically ranges from 40–120 um [31]. Therefore, the resolution of OFDI is theoretically sufficient for MNGCs to be visible. As such, it is not clear why the sensitivity for the detection of MNGCs was so low when compared with TAB. It may be a result of inadequate user experience, a lack of chromatic contrast between MNGCs and the surrounding tissue, or artifacts degrading the quality of the images. Image artifacts are largely avoidable but can be caused by inadequate blood flushing the vessel, air in the imaging catheter sheath, or eccentric wire positioning [32]. With greater user experience, simple post-imaging modification such as brightness or contrast adjustment, and the minimisation of image artifacts, it may be possible to improve the sensitivity of OFDI for detecting MNGCs. Alternatively, with sufficient raw data, automated image analysis (using edge detection and/or segmentation and the subsequent construction of recurrent neural networks) may achieve greater sensitivity than human interpretation of images.

Although FIEL is a common finding in GCA [33], as an isolated finding, it is of limited diagnostic significance owing to its low specificity and common presence as part of a normal aging process [34]. However, the high sensitivity that OFDI achieved in detecting FIEL is encouraging. Despite its low clinical specificity, it does represent a useful supplementary finding; when used in combination with other OFDI-derived measures (MIT > 0.20 mm and the presence of MNGCs) a high sensitivity (91.7%) and specificity (94.1%) in detecting histologically confirmed arteritis was achieved.

As with any novel imaging modality, observer skill takes time to develop. Despite this, the sensitivity and specificity that OFDI achieved in this study are promising. This sensitivity and specificity was achieved with the 16 mm segments of artery that were excised for histopathological examination and will therefore be subject to the same risk of skip lesions as TAB. Specimen length is itself known to be an independent prognostic factor for a positive TAB result and it is anticipated that ‘on table’ OFDI would be able to image a longer section of the artery [35]. The diameter of the Fastview Coronary Imaging Catheter is 0.87 mm, and therefore should be able to image the entire 2.5 to 5 cm length of the superficial temporal artery even if the lumen is narrowed by arteritic change [36, 37].

OFDI is not without shortcomings. In severely inflamed and narrowed temporal arteries, catheterisation may be very challenging. It is possible that TAB would still be required in such scenarios, though biopsy would likely have a high sensitivity in such instances. Furthermore, although OFDI images and results are instantaneously available, a delay in identifying suitable operating space and OFDI expertise may still cause delay. OFDI units are expensive, and the probes are single use and costly. However, the required equipment is increasingly available in cardiology units, and it is feasible that GCA OFDI could be done in the cardiac catheterisation laboratory.

Limitations of this study primarily pertain to the use of TAB as a gold standard investigation and the direct comparison with OFDI images. To prevent damage or disruption of the TAB specimens, OFDI had to be performed promptly after the biopsy was taken. The speed with which this was performed likely compromised the quality of the OFDI images. Although this study made a direct comparison between the parameters of fresh ex-vivo tissue (OFDI) with formalin-fixed tissue (TAB), it is not clear whether the intimal wall thickness remains constant in thickness and composition during the fixation process. Lastly, the intimal wall thickness on OFDI was calculated as a mean thickness along the vessel length, measured at points where the intima was most clearly visible and defined, whereas the intimal wall thickness on histology was measured at its thinnest point.

In conclusion, this study represents the first use of intravascular ex-vivo OFDI in the diagnosis of GCA. This proof-of-concept study demonstrates both feasibility and promising diagnostic potential. The next steps in the development of this technique involve testing the reproducibility of results across different users and testing the utility of OFDI in vivo.