Gender differences and changes in body composition during tapering of TNF blockers in patients with ankylosing spondylitis.

Women have been substantially underrepresented in studies of ankylosing
spondylitis (AS). This is unfortunate since there are important gender
differences in AS. Women appear to respond less well to treatment with
TNF-alpha inhibitors (TNFi), medication that is frequently used in AS.

In daily practise it becomes more and more common to taper the use of TNF
blockers in AS patients. The recently updated European (ASAS-EULAR)
recommendations recommend to taper TNFi in AS patients with sustained low
disease activity. A great proportion of the patients responds well to tapered
dosages. However studies on the subject mostly included male patients and it is
unknown if gender differences also play a role in the succes of treatment
reduction.

The fact that not all patients respond well to TNFi (during treatment and/or
during tapering) could be (partly) due to differences in body composition.
Adipose tissue is an important source of TNF-alpha and the amount and
distribution of adipose tissue is generally different for men and women.
Therefor, body composition could be associated with the risk of an AS flare
during the tapering of TNFi.

The current project will prospectively study the prognostic relevance of gender
and body composition in the (successful) tapering of TNFi.

Primary objective:
to assess gender differences in the risk of flaring after the tapering of TNF
inhibition.

Secondary objectives:
1. to assess gender differences in body composition in AS patients with
sustained low disease activity during TNF-blocking treatment.
2. to assess the association between body composition and the risk of flaring,
3. to evaluate changes in body composition, physical functioning,
cardiovascular risk profile, quality of life, drug trough levels and antidrug
antibodies after tapering.
4. to identify risk factors for disease flares after tapering.

A prospective cohort study in 190 AS patients with a sustained low disease
activity on TNFi. The TNFi will be tapered according to a predefined schedule.
The disease activity will be monitored at least every 3 months using clinical
and laboratory measures. Also the physical functioning, the global disease
burden and the cardiovascular risk profile will be evaluated every 3 months.
The (changes in) body composition will be assessed using anthropomethric
measures and a whole-body DEXA scan, before tapering and after 6 months. Blood
samples will be collected for a future study protocol focussing on changes in
pharmacokinetics and dynamics after TNFi tapering.

Patients will be followed up during 1 year. Patients that develop an AS flare
will restart on the original TNFi schedule.

The tapering schedule consists of doubling the dosage interval of the TNFi.
Patients that develop a flare will return to their original treatment schedule.
In addition, a whole body dual-energy X-ray absorptiometry (2 times), the AS
Performance-based Improvement test (the 'ASPI', a short physical functioning
test, every 3 months), the ASAS Health Index questionnaire (every 3 months) and
blood sampling (13.9 cc, during a regular venapunction, 2-3 times) will be
performed.

Patients that participate are at risk of an AS flare, resulting in temporarily
more pain and stiffness. However, according to the European guidelines the
current population would also be eligible for tapering in standard care, so the
current study does not add an additional risk. In most studies restarting the
original dose regimen is sufficient to rapidly reduce these complaints.

In this study we use a predefined tapering schedule. Theoretically this could
slightly increase the risk of an AS flare, in comparison to a personalized
tapering schedule. However, standardized schedules are the only investigated
(and evidence-based) tapering strategies and improve the scientific quality of
this study.

Therefor the additional burden caused by this study is thought to exist of:
- Whole body DEXA scans: 2 times, total radiation exposure of 0.008 mSv. This
is considered to be very low.
- Additional time investment on the outpatient clinic during regular visits
(for additional measures and DEXA scans), estimated to be 115 minutes in total.
- Additional blood sampling (13.9 cc, 2-3 times) during regular venapunctions.
- A risk of a temporary increase in AS related complaints (pain and fatigue),
caused by the ASPI test.