Assessment of disease activity of ankylosing spondylitis with [18F]Fluoride PET-CT.

Ankylosing Spondylitis (AS) is a chronic, inflammatory, rheumatic disease which
usually starts at an early age (< 40 years of age) and can result in
irreversible bone deformation and disability on the long term. The introduction
of anti-tumor necrosis factor (anti-TNF) therapy made a more effective
treatment of AS possible. TNF-blockers have an established comparable and
impressive beneficial effect on axial, joint and tendon inflammation, on
inflammatory serum parameters and on disease activity and function. In about
70% of the treated AS patients anti-TNF is successful. There is evidence that
response to therapy is greater in patients with earlier disease and less damage.
Therefore there is a need for sensitive imaging techniques to be able to select
patients with active disease in particular in earlier stages and to predict
therapeutic efficacy of expensive treatment with anti-TNF in a early phase.
Conventional X-rays and CT-scans still play an important role for determination
and monitoring of structural damage, but these irreversible changes occur only
after 5 years of complaints. MRI has been explored as advanced imaging
technique for detection of disease activity of AS, also in relation to
treatment. However, conflicting data on the sensitivity and specificity of MRI
in (suspected) spondylarthropathies have been published. Therefore, the precise
role of MRI in visualizing disease activity of AS, remains unclear.
Positron emission tomography (PET), is another interesting imaging technique for
assessment of disease activity of AS. PET allows sensitive imaging of
functional tissue changes (pathophysiology) in the whole body by targeting
binding sites. The visualisation of pathophysiology makes PET potentially
suitable for early detection of inflammatory processes, even before anatomic
changes appear. In addition, it allows quantification of disease activity in
order to accurately monitor therapeutic effects. Recently, PET-CT scanning was
introduced as hybrid imaging technique which combines the unique properties of
sensitive imaging of pathophysiology and anatomical CT imaging as reference. In
this way, PET-CT offers the opportunity to visualize (early) inflammatory
changes as well as (early) structural changes such as new bone formation.
Moreover, the specificity of PET by use of receptor targeting tracers may be
another advantage for assessment of disease activity of AS. Since the definite
pathogenesis of AS is still not clear and different joint structures (synovial
tissue, bone marrow, entheses, ligaments) may be involved in inflammatory sites
in AS, it is still not known which foci primarily represent disease activity.
In a recent pilot study setting, a subpopulation of 2 patients showed that the
bone tracer [18F]fluoride was superior to the inflammation tracers [18F]FDG and
[11C](R)PK11195 for depicting disease activity of AS. The present project will
further evaluate the potential of the [18F]fluoride tracer in AS patients
before and after anti-TNF therapy. Furthermore, in a small sub study of 2
patients, the possibility for obtaining representative bone biopsies of active
bone lesions as depicted with PET-CT will be investigated for future pathogenic
research.

1.To investigate if [18F]Fluoride PET-CT is a potential imaging technique for
assessment of (changes in) disease activity of ankylosing spondylitis on
baseline and after anti-TNF therapy (with MRI and clinical outcome as
reference).

Sub-study in 2 patients:

2. To evaluate if it is technically possible to obtain representable bone
biopsies under CT guidance from hotspots depicted with [18F]Fluoride CT scans.
This procedure could be used in a future study to investigate the relation
between lesions on [18F]Fluoride PET-CT and histology.

Ten AS patients with high disease activity (Bath Ankylosing Spondylitis Disease
Activity Index (BASDAI) score* 4) who will start with anti-tumor necrosis
factor (anti-TNF) therapy will be included for a [18F]Fluoride PET-CT scan of
the total spine as well as of the sacroiliac (SI) joints at baseline. Besides
PET-CT, a MRI scan of the spine and SI joints will be performed. The different
scans will be made within one week. The imaging procedure will be repeated 12
weeks after treatment. Anti-TNF treatment will be part of clinical care.
Clinical disease activity will be monitored up to 24 weeks of anti-TNF
treatment, including determination of C* reactive protein (CRP) levels. In a
small sub study, two additional patients with the same characteristics as
described above will be included for a bone biopsy procedure following the
[18F]Fluoride PET-CT scan and MRI of the axial skeleton. These two patients
will not be included for clinical and imaging follow-up because of interference
of bone biopsy with follow-up of lesions on the scans and to limit the burden
on the patients.

Radiation exposure
The effective dose equivalent (EDE) of a PET-scan with injection of 100 MBq
[18F]fluoride is 1.7 mSv. Including low dose attenuation CTs (8 mSv), the total
radiation exposure of the two series of PET-CT scans, baseline and 12 weeks
after treatment, result in a total radiation burden of 11.4 mSv. For the two
patients that will be scanned once with [18F]Fluoride PET-CT and obtain one
diagnostic CT of one segment for bone biopsy, the radiation burden will be 1.7
mSv plus 5.5 mSv is 7.2 mSv per patient. For comparison: the mean effective
dose of a diagnostic CT-abdomen is 11 mSv (data RIVM). This radiation burden is
about 5 times the yearly natural background radiation dose in the Netherlands.
According to the ICRP-62 model, the risk level corresponds to *moderate*, while
the social benefit is regarded as *substantial*.


Vena puncture
The PET tracers and the gadolinium-contrast for MRI will be administered
intravenously. The necessary vena puncture is similar to that applied for blood
withdrawal in clinical practice.

Discomfort during scanning
It may be uncomfortable to lie motionless on the scanning bed of the PET-CT and
the MRI scanner. For some patients, the scanning may be anxious. To reduce
anxiety and discomfort as much as possible, patients will be made acquainted
with the surroundings beforehand. In addition, the staff will be present during
scanning and can remove the patient from the scanner if requested.

Risks of bone biopsy of axial skeleton
General risk of complication risk is 0.5% (in experienced hands). A careful
preparation is most important to reduce complications. To further limit
complications, bone biopsies will not be taken of the anterior vertebral
column. The most common risk is post biopsy venous bleeding without other
complications.

Benefit and group relatedness
Early diagnosis of AS and hence an early start of therapy as well as prediction
of therapeutic outcome will contribute to increase the therapeutic efficacy.
For these clinical needs, sensitive imaging techniques are required. Our
previous pilot data indicate that [18F]Fluoride PET-CT imaging seems to be a
potential image tool for assessment of (changes) of disease activity of AS by
the novel approach of targeting
active bone sites. This will be further addressed in the current study
protocol.