[18F]Fluoride PET-CT imaging for detection and monitoring of bone formation in spondyloarthritis

One of the hallmarks of disease activity in spondyloarthritis (SpA), a spectrum
of rheumatological disease including ankylosing spondylitis (AS) and psoriatic
arthritis (PsA), is new bone formation. Enthesitis and bone formation are
related to functional disability on the long term. SpA is a complex disease, as
evidenced by the involvement of axial and peripheral articular structures,
extra-articular manifestations, presence of co-morbidities such as osteoporosis
and vascular inflammation and the histopathological combination of
inflammation, tissue destruction, and new tissue formation. Mechanistic
understanding of which *targetable* pathways steer these different disease
manifestations is required to optimize and tailor treatment to all these
different facets of the disease.

Both TNFα and IL-17 are pivotal pathogenic cytokines in SpA. Therapeutic
inhibition of each of these cytokines leads to both significant improvement of
clinical symptoms and suppression of inflammation in SpA. Studies show that
anti-TNF decreases inflammatory activity, and may inhibit progression of bone
formation after longer use. Anti-IL-17 treatment, such as Secukinumab, has a
very promising profile to inhibit not only inflammatory activity, but
potentially also bone formation.

In order to investigate therapeutic effects of Secukinumab on enthesitis and
related bone formation, sensitive imaging techniques are required for
monitoring early in the course of treatment. Conventional X-rays and CT-scans
still play an important role for determination and monitoring of structural
damage, but these techniques have limitations. CT-scans do not allow assessment
of the whole skeleton in one imaging session, and X-rays are more suited to
provide information on long-term changes in bone formation. Both MRI and
ultrasound (US) can be applied for evaluation of inflammatory activity, however
US is limited to more superficial, peripheral sites that are accessible by this
technique, and MRI is less sensitive for bone formation imaging in SpA.

Positron emission tomography (PET) is a promising alternative for bone
formation imaging. The technique allows sensitive and quantitative imaging of
functional tissue changes in the whole body by targeting specific binding
sites. The visualisation of pathophysiology using specific tracers makes PET
potentially suitable for early detection of disease activity, even before
anatomic changes appear. In addition, it allows quantification of disease
activity in order to accurately monitor therapeutic effects. Recently, our
group found that disease activity of AS on PET-CT was clearly depicted with the
tracer [18F]Fluoride with obvious superior targeting as compared to the
reference tracers. [18F]Fluoride uptake in bone reflects local blood flow and
regional osteoblastic activity because uptake takes place in the form of
hydroxyapatite crystals, which form the mineral fluorapatite within the bone,
especially at sites of bone remodelling. A study currently in progress of
publication by our group has shown the ability of [18F]Fluoride PET-CT imaging
of bone formation in AS to predict response to anti-TNF treatment.

The aim is to investigate the therapeutic effects of Secukinumab on bone
formation in SpA patients by using [18F]Fluoride PET-CT imaging, and to
investigate cellular and molecular pathology in bone formation.

A prospective cohort study in 48 patients with spondyloarthritis (either PsA or
AS). The study is devided into several sub-groups:
- Patients who receive a [18F]Fluoride whole body PET-CT at baseline prior to
Secukinumab treatment and after twelve weeks of treatment. This group is
subdivided in two cohorts:
o Clinically active PsA patients (n = 15) with clinical indication for
Secukinumab treatment
o Clinically active AS patients (n = 15)
- Clinically active PsA patients who receive a [18F]Fluoride whole body PET-CT
at baseline prior to anti-TNF treatment and after twelve weeks of treatment (n
= 10).
o This group will be used as a reference treatment group; for AS we already
have reference anti-TNF [18F]Fluoride PET data available.
- Patients with clinically active AS (n = 8) who receive a [18F]Fluoride whole
body PET-CT at baseline and PET-CT guided bone biopsies, before starting with
biological therapy, or before/during NSAID and/or DMARD therapy.

Patients will receive a PET-CT scan at baseline (before start of Secukinumab or
anti-TNF treatment) and a PET-CT scan after 12 weeks of treatment.
Additionally, a group of 8 patients included in the sub-study will receive one
PET-CT scan and a bone biopsy.

The total radiation burden will be about 10.4 - 10.8 mSv. The general risk of
complications caused by bone biopsies within this patient group is estimated
0.5 - 1% ,the most common risk being post biopsy venous bleeding without other
complications.