Fluoride PET-CT imaging for the detection of bone formation in (very) early and preclinical spondyloarthritis.

Axial spondyloarthritis (axSpA) is a chronic inflammatory arthritis with a
prevalence of 0,5-1% in Western countries. The disease starts in young adults,
mainly males, between the age of 20-40 years and is characterized by
inflammation and new bone formation with structural damage of the spine. This
results in pain and limited mobility of the spine with a high impact on
functioning in daily life. The disease entity comprises both non-radiographic
axSpA where no structural changes are seen on conventional imaging as well as
radiographic axSpA also referred to as ankylosing spondylitis where structural
lesions of the spine or sacroiliac joints are present. Despite recent advances
in therapeutic options for axSpA it is still not possible to sufficiently
control inflammation in all patients, as only 60- 70% of the patients respond
of whom 30% only partially. Disease remission is only achieved in about 20% of
the patients. In addition, so far no effects on halting new bone formation have
been shown. This results in functional impairment and loss of quality of life
for most axSpA patients.

Possibly this limited efficacy can be explained by: 1.Available treatments are
not aimed at the right targets to stop inflammation and new bone formation.
2.The diagnostic delay disables us to initiate treatment early enough to halt
the chronic autonomous inflammation and new bone formation sufficiently.

To target inflammation and new bone formation more successfully it is essential
to increase the insight into the pathogenic processes that initiate and drive
inflammation and new bone formation in axSpA, and make an earlier diagnosis.

Both inflammation and new bone formation can be visualized by various imaging
modalities. Active inflammatory lesions of the spine and SI joints can be seen
on MRI. We have previously shown that with [18F]Fluoride PET-CT it is possible
to study the active process of new bone formation. This is in contrast to
X-rays of the spine or SI joints with which only end stage destruction can be
visualized. It was confirmed by histology that [18F]Fluoride PET-CT lesions in
ankylosing spondylitis patients represent active local osteoid formation,
representative of new bone formation, and that these lesions are responsive to
TNF treatment. This underlines that [18F]Fluoride PET-CT is a robust method to
evaluate bone bone formation in axSpA patients.

In axial spondyloarthritis it is hypothesized that molecular processes that
trigger inflammation and new bone formation are initiated even before the
disease becomes clinically manifest This phase is called the pre-clinical
phase.
First-degree relative (FDR) of axSpA patients have an increased risk of
developing disease compared to the general population. Familial studies showed
that the recurrence risk of AS in HLA-B27 positive FDRs of AS is 20%. When
including early (pre-radiographic) disease stages of SpA, this recurrence risk
in HLA-B27 positive FDRs of axial SpA is approximately 30-40%. We have
previously shown that indeed subclinical signs of spondyloarthritis can be
observed in upto 25% of these at risk FDR of HLA-B27+ axSpA patients. Interim
analysis of 1 year follow up in 123 FDR showed that 6% developed clinically
manifest disease in the first year. These data indicate that there is a high
incidence of pre-SpA in these FDRs and that disease incidence is much higher
than in the general population which thus supports the rational of studying
this population at risk.

Of importance, pwe have shown in healthy first-degree relatives (FDRs) of
HLA-B27+ xSpA patients at risk of developing AxSpA, that 20% had sacroiliitis
on MRI of the SI-joints (but no clinical diagnosis of AxSpA). Underlining that
in at risk individuals already imaging abnormalities suggestive of
(subclinical) inflammation can be observed. So far, no data on new bone
formation in at risk individuals is available.

To investigate if subjects with an increased risk of developing
spondyloarthritis have evidence of bone formation on [18F] Fluoride PET-CT.

A cross-sectional, monocenter PET study in 20 patients with an increased risk
of developing axial spondyloarthritis.

The total radiation burden will be about 4.0 mSv.