Bone formation rather than inflammation reflects Ankylosing Spondylitis activity on PET-CT: a pilot study

Ankylosing spondylitis (AS) is a chronic, inflammatory, rheumatic disease that usually starts at an early age and can result in irreversible bone deformation and disability in the long term. AS is characterized by inflammatory back pain, limited motion of the spine, and sacroiliitis on plain radiography. Peripheral arthritis and enthesitis may also be prominent features [1]. Patients with AS are often treated with non-steroidal anti-inflammatory drugs (NSAIDs) because they stabilize disease activity over time and, in addition, can reduce radiographic progression [2]. However, with the introduction of anti-tumor necrosis factor (anti-TNF) therapy, a more effective treatment of AS became possible. Patients with AS seem to benefit most if treatment with TNF blockers is started early in the disease course, particularly when started at a younger age [3, 4]. Therefore, it is important to diagnose this disease early. Until recently, plain radiographs were obligatory for the diagnosis of AS, according to the modified New York criteria [5]. The disadvantage of this imaging technique is that it usually takes many years before the disease comes to full expression and definite radiographic sacroiliitis appears [5]. Consequently, the diagnosis is often delayed by 5 to 10 years, especially in patients with an early or incomplete clinical picture [1, 6, 7]. To enable earlier diagnosis, highly reliable and sensitive imaging techniques are needed.

Nowadays, magnetic resonance imaging (MRI) is believed to be a sensitive imaging modality for the detection of sacroiliitis and inflammation of the spine in early AS. MRI detects (early) inflammation by visualization of tissue edema or enhanced gadolinium contrast uptake or both. However, these imaging findings are non-specific indicators of increased free water content and increased vascularization, respectively [8, 9]. Moreover, chronic AS changes, such as new bone formation in the spine (syndesmophyte formation), tend to be less well visualized on MRI than on radiographs [10]. Finally, although validated scoring methods are available, conflicting data on the sensitivity and specificity of MRI in (suspected) spondylarthropathies have been published [6, 11‐14]. Therefore, the precise role of MRI in visualizing disease activity of AS has not yet been fully elucidated.

Positron emission tomography (PET) is another interesting imaging technique for the diagnosis of AS. PET allows sensitive imaging of functional tissue changes (pathophysiology) in the whole body by targeting binding sites [15]. The visualization of pathophysiology makes PET potentially suitable for early detection of inflammatory processes, even before anatomical changes occur. Thereby, PET allows specificity through the use of receptor targeting tracers and allows quantification of disease activity in order to accurately monitor therapeutic effects [16]. Recently, PET-computed tomography (PET-CT) scanning was introduced as a hybrid imaging technique that combines the unique properties of sensitive imaging of pathophysiology and anatomical CT imaging as a reference [17]. In this way, PET-CT offers the opportunity to visualize (early) inflammatory changes as well as (early) structural changes such as new bone formation, which is hard to detect on MRI.

The definite pathogenesis of AS is still not clear, and different joint structures may be involved in inflammatory sites in AS [18]. Therefore, different targets for the PET tracers have to be taken into account. Synovial tissue, bone marrow, entheses, and ligaments can be affected in AS [19‐21] and may need different specific tissue PET tracers. PET studies in patients with rheumatoid arthritis (RA) clearly revealed inflamed synovial tissue through the use of the glucose analogue [¹⁸F]-fluoro-2-deoxy-D-glucose ([¹⁸F]FDG), visualizing increased metabolism in synovial tissue [16, 22, 23], and the macrophage tracer PK11195 [(R)-1-(2-chlorophenyl)-N-methyl-N(1-methyl-propyl)-3-isoquinoline carboxamide] ([¹¹C](R)PK11195) [24]. [¹¹C](R)PK11195 binds with high affinity to peripheral benzodiazepine receptors, which are expressed mainly on macrophages [25]. Since macrophage-rich inflammation has been demonstrated in patients with AS [26], both [¹⁸F]FDG and [¹¹C](R)PK11195 may be interesting tracers for detection of disease activity of AS. In addition to inflammation tracers, the bone tracer [¹⁸F]fluoride may have potential for AS imaging since AS is characterized by syndesmophyte formation and ankylosis in vertebral column and sacroiliac (SI) joints. [¹⁸F]Fluoride uptake in active bone reflects local blood flow and regional osteoblastic activity [27, 28]. Indeed, [¹⁸F]fluoride appeared to be a potential tracer for imaging of active bone sites in a small group of patients with AS [29].

The objective of this pilot study was to investigate the potential of PET-CT for imaging AS activity by the investigation of three different tracers in a stepwise approach with MRI and conventional radiographs as references for PET-CT data. Inflammation tracers [¹⁸F]FDG and [¹¹C](R)PK11195 were studied in patients with AS with low and high disease activity, and these inflammation tracers were compared with the bone tracer [¹⁸F]fluoride in additional patients with high disease activity.

Results of this pilot study show the potential of PET-CT imaging of AS activity. Targeting of bone formation appears to be the most promising approach to visualize AS activity. Inflammation tracers ([¹⁸F]FDG and [¹¹C](R)PK11195) seem to be less useful for imaging of AS than for imaging of active RA [16, 22‐24].

There may be several explanations for the discrepancy between [¹⁸F]FDG, [¹¹C](R)PK11195, and [¹⁸F]fluoride PET-CT findings. First of all, since the definite pathogenesis of AS still has to be elucidated, it is unknown which target site for imaging of AS is optimal [18]. Entheses are of special interest, and synovitis seems to be less prominent in AS compared with RA [20]. In addition, syndesmophyte formation and ankylosis, hallmarks of AS, reflect local osteoblastic activity. Our PET-CT findings suggest that bone formation (for example, osteoblastic activity) may be a more prominent feature of AS activity than inflammation. The present PET-CT results with the different tracers, therefore, reveal interesting data that may provide insights into the pathogenesis of AS.

Secondly, tracer biodistribution may be related to varying tracer characteristics. Uptake mechanisms are different for each tracer. In (red) bone marrow, [¹¹C](R)PK11195 PET scans showed a diffuse increased uptake pattern which could possibly overwhelm potential small focal activity spots in or around bone. [¹⁸F]FDG is probably a useful marker for synovitis [16, 22, 23] and osteomyelitis [31, 32] but may be less suited for detection of (non- or low-inflammatory) bone formation in AS [33‐37]. In general, [¹⁸F]FDG seems to be more useful for detection of osteolytic than for osteoblastic lesions [38]. [¹⁸F]Fluoride, on the other hand, reflects osteoblastic activity because of the tracer's uptake into hydroxyapatite crystals, which form the mineral fluoroapatite within bone, especially at sites of bone formation [27, 28, 39]. Our positive results with [¹⁸F]fluoride PET-CT in both vertebral column and SI joints of patients with AS correspond with [¹⁸F]fluoride PET-CT findings of Strobel and colleagues [29] in SI joints of patients with AS and osteo-articular [¹⁸F]fluoride findings of Ben Ali and colleagues [40], indicating that [¹⁸F]fluoride is a potential tracer for active bone sites in AS.

A third explanation for the differences in uptake of the three tracers might be related to patient selection. Patients were categorized in low or high disease activity group according to the BASDAI level. BASDAI is a patient questionnaire commonly used to assess disease activity in AS. Congruent imaging results (no active lesions) were found in four out of five patients with low disease activity, corresponding to BASDAI measurements. In contrast, in patients with high disease activity (BASDAI ≥ 4), three out of seven patients with AS did not show any active inflammation on MRI. This corresponds to findings of others who did not find any association between MRI and clinical data [41, 42]. Therefore, high BASDAI scores with negative MRI may be more related to secondary degenerative changes and ankylosis rather than active inflammation. This is supported by the finding that six out of seven patients with high disease activity showed bony structural lesions in one or more vertebral bodies; at least 50% of these lesions had degenerative characteristics. Indeed, nowadays, the BASDAI is criticized, and recent studies express the belief that the ankylosing spondylitis disease activity score (ASDAS) is a better selection criterion than BASDAI [43‐45]. Furthermore, NSAIDs were continued if used at inclusion. In theory, NSAID use may have suppressed inflammatory activity; however, Gaspersic and colleagues [46] showed that anti-inflammatory drugs have no influence on monitoring AS with MRI. In our study, NSAIDs did not seem to influence [¹⁸F]fluoride uptake in active lesions since PET-CT scans depicted 17 hotspots in the two patients scanned with this tracer.

PET-CT data were compared with MRI and conventional radiographs as references. Focusing on the two patients additionally scanned with [¹⁸F]fluoride PET-CT, most MRI lesions corresponded to lesions with [¹⁸F]fluoride uptake on the PET scan. Additionally, two active [¹⁸F]fluoride PET-CT lesions in SI joints showed subchondral fatty marrow infiltration on MRI. Although the exact significance of subchondral fatty marrow infiltration is not yet clear, it is believed to be a late structural change due to chronic inflammation in AS [47].

On the other hand, in 11 out of 17 [¹⁸F]fluoride PET-positive lesions, structural changes were found on conventional x-rays. (Secondary) degenerative changes such as sclerosis and facet arthrosis may result in a positive [¹⁸F]fluoride signal. However, these lesions could also reflect chronic AS disease activity (the mean symptom duration of patients 11 and 12 was 22 years). Indeed, degenerative changes as well as other structural changes such as squaring and syndesmophyte formation can coexist with chronic inflammation [48]. Finally, the observed [¹⁸F]fluoride hotspots in the sternum and shoulder seemed to correlate with clinical symptoms of patients, again underlining the potential of [¹⁸F]fluoride PET-CT to visualize active sites in AS.

Despite the limited number of patients investigated in this study, our PET-CT results suggest that AS activity was reflected by bone formation and not by inflammation, and this finding throws an interesting light on the pathogenesis of the disease. In addition, [¹⁸F]fluoride PET-CT seems to be a promising imaging technique for detecting active lesions in the spine and SI joints of patients with AS, but the definite value of [¹⁸F]fluoride PET-CT as a diagnostic tool for assessment of AS activity needs to be further explored in future studies with larger cohort(s) of patients with AS.