¹⁸F-sodium fluoride PET-CT visualizes both axial and peripheral new bone formation in psoriatic arthritis patients

Psoriatic arthritis (PsA) is a chronic, inflammatory, musculoskeletal disease associated with psoriasis [1] and several musculoskeletal manifestations, including arthritis, dactylitis, spondylitis and enthesitis. The last of these is a key pathophysiological feature that negatively affects the quality of life [2‐6]. Previous data indicate that enthesitis underlies a variety of manifestations of PsA [7]. A synovial-entheseal complex has been described, pointing at a close relationship between an enthesis and the synovial membrane, suggesting that entheseal abnormalities might trigger secondary joint synovitis [8]. In addition, enthesitis plays a relevant role in dactylitis and axial disease activity as well [9]. Detection of enthesitis may therefore enable early assessment of PsA disease activity, which in turn may lead to the start of early treatment that can potentially improve all disease manifestations of PsA [8, 9].

Clinical assessment of enthesitis is challenging and has limited accuracy, as it is based only on the presence of tenderness and general soft-tissue swelling [6]. Moreover, clinical assessment is often unable to identify bursitis, erosions or calcifications [10, 11]. Advanced imaging techniques such as ultrasound (US) and magnetic resonance imaging (MRI) have shown promise to sensitively detect entheseal inflammation [12‐14]. However, limitations of these techniques have also been described. In US, bodyweight and repetitive physical activity or overloading can influence structural entheseal lesions and can thus bias the observation of disease-related enthesitis [15‐17]. In addition, this technique cannot be used to detect axial and more deeply located enthesitis. As for MRI, conventional MRI is limited to the selected field of view [18]. Whole-body MRI (WBMRI) may be an alternative, but the image quality and reproducibility of distal peripheral sites are low [19]. Moreover, the slice thickness (5–6 mm) causes a lower readability of some entheses, such as at the costochondral joints [20, 21]. Structural entheseal lesions, which are characterized by periosteal proliferation and new bone formation, have been identified in psoriasis patients without evidence of PsA using high-resolution peripheral quantitative computed tomography (HR-pQCT) and are described as an independent marker for later PsA development [22, 23]. However, HR-pQCT is mainly suitable for small body parts due to its limited field of view.

Positron emission tomography (PET) may be a promising alternative for detection of disease activity in the whole body since it combines picomolar depiction of pathologic processes with anatomical low-dose computed tomography (CT) imaging as a reference [24, 25]. By application of specific tracers, molecular targets of interest can be visualized. One such tracer is ¹⁸F-sodium fluoride (¹⁸F-NaF), which depicts new bone formation as a consequence of osteoblastic activity. New bone formation is an important hallmark of spondyloarthritis [26]. We and others have recently demonstrated that ¹⁸F-NaF PET allows for sensitive and specific imaging of new bone formation in ankylosing spondylitis (AS) patients [27, 28]. Since enthesitis activity in PsA can be accompanied by new bone formation (e.g. peripheral formation in osteophytes and axial formation in syndesmophytes), ¹⁸F-NaF PET may enable sensitive detection of skeletal disease manifestations in PsA.

Therefore, the primary aim of this study was to determine the feasibility of whole-body ¹⁸F-NaF PET-CT in clinically active PsA patients to depict new bone formation (as reflection of disease activity) at peripheral joints and entheses. Secondly, we aimed to describe ¹⁸F-NaF findings in the axial skeleton of clinically active PsA patients.

This is, to our knowledge, the first feasibility study on whole-body ¹⁸F-NaF PET-CT imaging in PsA patients. Our data demonstrate that ¹⁸F-NaF PET-CT can detect new bone formation, at sites of peripheral joints and various entheses and in dactylitis. In addition, several lesions with ¹⁸F-NaF uptake, suspect for PsA activity, could be demonstrated in the axial skeleton. Taken together, these findings suggest that ¹⁸F-NaF PET-CT may be a novel clinically valuable tool to detect whole-body disease activity of PsA reflected by new bone formation in all disease domains of PsA, depicted in one scan.

Several studies have aimed to visualize disease activity of PsA. An association has been described between enthesitis and extensive adjacent osteitis in both peripheral joints and the spine and is most likely the base for bone formation and related ¹⁸F-NaF PET tracer uptake [27, 35, 36]. Thus far, ¹⁸F-NaF PET-CT was only investigated previously in one other study of the DIP joints in a limited number of PsA patients, showing tracer uptake in the bone-enthesis-nail complex [37]. In our study, we have shown that ¹⁸F-NaF PET-CT can highly sensitively depict the activity of all PsA manifestations in one whole-body scan. In this perspective, the PET-CT tool also has advantages over currently applied US and MRI in PsA, as is outlined in “Introduction” [19, 20]. Moreover, the technique visualizes molecular new bone formation, possibly another aspect of the disease activity than US and MRI that primarily image inflammatory activity. Therefore, ¹⁸F-NaF PET-CT and MRI/US may be complementary in providing objective PsA disease activity assessment. In addition, although direct comparative studies between ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) and ¹⁸F-NaF in PsA are lacking, a comparative study by our group between ¹⁸F-FDG and ¹⁸F-NaF in AS patients revealed that disease activity on PET-CT is superiorly visualized by imaging new bone formation rather than inflammation [38]. As both PsA and AS are part of the spondyloarthropathy (SpA) spectrum, based on current studies, ¹⁸F-NaF seems to be the preferred PET tracer over ¹⁸F-FDG with regard to disease activity visualization of SpA. Whether new bone formation precedes, co-exists (dependently or independently) or follows inflammatory activity in PsA still needs to be unravelled [39]. Imaging studies with the different modalities and associated histological validation could support future pathogenetic research.

We observed a high number of clinically asymptomatic peripheral joint and entheseal lesions with ¹⁸F-NaF PET enhancement. These results are in line with those of Tan et al. who observed more PET enhancement in asymptomatic DIP joints in PsA patients as well, compared to healthy controls [37]. In fact, a high level of discrepancy between PET-CT and clinical findings may be expected, since ¹⁸F-NaF PET-CT visualizes molecular new bone formation and clinical assessment is directed at inflammatory activity. As stated above, the association of inflammation and new bone formation in PsA is not clear yet, and may occur (partly) independently and/or at different time points [40‐43]. Several data suggest highly sensitive detection of subclinical disease activity by¹⁸F-NaF PET-CT that may precede clinical symptoms and/or radiological abnormalities/progression of PsA. Positive lesions in anterior corners of vertebrae on ¹⁸F-NaF PET-CT in spondyloarthritis patients have been found to be associated with local syndesmophyte formation 2 years later in time [28]. In addition, bone remodelling has already been demonstrated at the entheses in MCP joints in psoriasis patients without clinically diagnosed PsA (yet) [42]. Apart from depiction of another disease activity aspect by ¹⁸F-NaF PET-CT than clinical assessment, there are probably also other reasons for disagreement between the two. This is also reflected by reported low-moderate agreement between clinical and US and MRI imaging findings that primarily focus on inflammatory activity in joints and entheses [12, 20, 44‐47]. Although clinical joint and enthesis counts are validated outcome measures, several limitations are known. Enthesitis is generally difficult to examine clinically in a reliable way, since this is only based on pain provoked by local pressure, and deeper located entheses cannot be assessed by clinical examination at all [6]. In addition, it is a general finding in clinical practice that certain joints, including those in midfoot and IP joints in toes, are difficult to assess for presence of disease activity. Especially the assessment of swollen joints often has a very poor inter-observer agreement [48, 49] while swollen joints in particular are associated with radiographic joint progression and are therefore crucial to include in disease activity assessments [50]. ¹⁸F-NaF uptake in asymptomatic peripheral sites may also be related to local degenerative changes, as these can be ¹⁸F-NaF positive as well [51, 52]. However, our analysis of the ¹⁸F-NaF PET-CT scans using the low-dose CT to screen for major degenerative/osteoarthritis changes revealed that the majority of peripheral joints with ¹⁸F-NaF tracer uptake did not show major osteoarthritis but partly showed typical PsA structural abnormalities including bone formation, erosions and pencil-in-cup deformation. In addition, potential bias of degenerative related ¹⁸F-NaF uptake in peripheral joints is less likely, as ¹⁸F-NaF-positive lesions were also observed in younger patients without any signs of local degeneration on low-dose CT. Moreover, in previous longitudinal ¹⁸F-NaF PET-CT data we collected in AS patients, we found that ¹⁸F-NaF uptake was responsive to anti-tumour necrosis factor (aTNF) treatment in typical AS spine lesions, which supports the potential of ¹⁸F-NaF PET-CT to image molecular new bone formation as part of spondyloarthritis disease activity [27]. Together, the current study data point at clinical and subclinical detection of PsA activity in bone by ¹⁸F-NaF PET-CT. The clinical relevance of asymptomatic PET lesions in PsA should be further addressed in longitudinal studies, relating PET outcome with clinical and radiological follow-up over time.

Axial involvement in PsA is associated with worse outcomes, but is an often underdiagnosed aspect of the disease [53‐55]. In 20–25% of patients, subclinical axial involvement is present, without clinical features demonstrating that ¹⁸F-NaF PET-CT scans can depict lesions in the spine and SI joints in often clinically asymptomatic patients, indicating that this imaging technique visualizes signs of axial bone formation, even before clinical symptoms arise. An important differential diagnosis for this uptake, however, is local degeneration. Nevertheless, approximately 20% of our spinal lesions were identified as likely PsA related (lacking major primary degenerative changes on low-dose CT), although some misclassification cannot be ruled out since we used (non-diagnostic) low-dose CT for interpretation. These findings should be further explored in longitudinal studies. In fact, in our previously published ¹⁸F-NaF PET-CT study in ankylosing spondylitis patients, we found that in particular PET-positive costovertebral joints and SI joints were responsive to anti-TNF treatment and could distinguish between clinical responders and non-responders, pointing at detection of SpA-related lesions in the axial skeleton [27]. The lack of comparative radiological imaging with diagnostic anatomical modalities in our study precludes any in-depth recognition of disease-related uptake patterns versus degenerative-related uptake patterns. Nonetheless, our aim was to describe, as a first whole-body feasibility study, the ¹⁸F-NaF findings in the axial skeleton of clinically active PsA patients. Future research should focus on differentiation between typical PsA and typical degenerative lesions in order to exclude the degenerative lesions from analysis on PsA related disease, resulting in a comprehensible reflection of the extent of disease related bone formation in PsA patients.

Apart from the above-described lacking comparative diagnostic anatomical modalities, this feasibility study included some other limitations. Firstly, this study was performed in a small group of PsA patients and further validation of our results in larger cohorts is needed. Secondly, the study is limited by the lack of clinical information on the DIP, midtarsal and the IP joints of the feet. In these joints, PET positivity was frequently found; thus, the comparison of PET and clinical findings may have had a different outcome for these joints.

¹⁸F-NaF PET-CT scans can visualize new bone formation, pointing at local PsA activity, at all peripheral disease activity sites and possibly in the axial skeleton. ¹⁸F-NaF PET-CT may add information to clinical disease activity assessment, reflected by a high number of clinically negative, PET-positive sites on top of concordant findings.