Prevention of the progression of very early symptoms into ankylosing spondylitis

Ankylosing Spondylitis (AS) belongs to a group of diseases which are
referred to as Spondyloarthropathies (SpA), with a prevalence of 1.0% in
Caucasians and onset early in life (25-40 years of age). AS as the prototype of
an SpA, is a chronic inflammatory disabling rheumatic disease. The diagnosis of
AS requires at least one criterion out of three (Inflammatory back pain (IBP),
limited spinal motion, decreased chest expansion) and sacroiliitis on X-ray,
which is due to chronic inflammation of the sacroiliac (SI) joints and
vertebral column. The inflammatory process can result in destruction of the
vertebral column leading to serious postural deformities. Extra spinal
manifestations of the disease consist of arthritis of the peripheral joints
(especially knees, shoulders, and hips) and enthesitis. The diagnosis of AS is
based on the modified New York criteria. It requires radiographically proven
sacroiliitis grade 2-4 bilaterally or grade 3-4 unilaterally for a definitive
diagnosis. The radiographs are often normal when the first symptoms arise and
it usually takes several years before definite radiographic sacroiliitis
appears. The mean delay to diagnosis is usually 5-10 years. Therefore is
important to diagnose AS in an earlier stage, especially before the onset of
irreversible radiographic changes. About 16% of patients with IBP already
appear to have radiographic sacroiliitis and almost 30% show inflammation of
the SI-joint on MRI. Inflammation on MRI is a prognostic factor for the
development of AS; it has a positive predictive value of 60% for the
development of radiographic sacroiliitis after 3 years in patients with IBP.
Patients with IBP and additional early symptoms of disease, are most likely to
progress into AS (about 60% in ten years). This group of patients can be
diagnosed with a high probability of at least 90% when IBP and at least two
other SpA characteristics are present (especially inflammation on MRI).
Therapy was, until five years ago, symptomatic with non-steroidal
anti-inflammatory drugs (NSAIDs) and physiotherapy. As a second line approach,
the disease modifying antirheumatic drugs (DMARDs) have been used. However, in
contrast to RA, the effect of DMARDs in AS is less impressive. A
breakthrough in therapy are the tumor necrosis factor alpha (TNF alpha)
blockers. Etanercept proved to be effective on almost all clinical features of
AS. Furthermore, signs of inflammation as seen on MRI also decreased during
anti-TNF therapy. Patients with shorter disease duration showed a better
response to the TNF-blockers than patients with longer disease duration.In
summary with regard to AS a study to prevent the progression of inflammatory
back pain into AS seems to be neededfor the following reasons. The prevalence
of AS is estimated about 1%, it starts at a relatively young age and the burden
of the disease is high. Moreover, patients with a high risk of developing AS
can be identified at a very early stage and effective therapy has become
available before irreversible changes occur. All ingredients are available now
to start an effort in order to prevent the onset of AS.

The general aim of this project is the primary prevention of the development of
AS in patients with IBP, additional (SpA) features and inflammation on MRI of
the SI joint and/or spine (but still no sacroiliitis on X-ray) by giving them,
a short period, anti-TNF therapy. Since the effect of a successful intervention
can only be measured after several years, the primary (but short-term) focus is
the decrease of the inflammatory abnormalities visible on MRI of the SI-joint
and/or spine after 16 weeks of etanercept therapy in comparison to placebo
treatment.
The primary objective of this study is the short-term clinical improvement and
the long-term delay in clinical deterioration after etanercept therapy in the
(preclinical AS) patients and therefore we look at the progression of early
symptoms into AS, clinically. This will be done by measuring the ASAS 20%
response criteria and by other clinical response criteria such as the BASDAI,
BASG, BASFI, acute phase reactants, after 16 weeks, 6 months and after 1, 2 and
3 years.
The secondary objective of this study is to reverse the inflammatory
abnormalities visible on MRI in (preclinical AS) patients without sacroiliitis
(or grade 1) on X-ray with short-during etanercept therapy. For this purpose
MRI scans will be made of the SI-joint and spine after 16 weeks (short term),
and after 6 months (long term).
Another secondary focus of this study is the progression into AS both on short
and long term, measured by the degree of radiological damage visible on X-ray
after one and three years.
The ultimate goals (and secondary objective) of this study are: to prevent or
inhibit the radiological progression with etanercept therapy compared with
placebo after 3 years and to lower the incidence of AS in this group of high
risk individuals

The study is designed as a randomized, double-blind, placebo-controlled trial.
After inclusion patients are randomly assigned to the etanercept- or
placebo-arm of the study in a 1:1 ratio. During 16 weeks etanercept (dosage 25
mg) or placebo will be given twice a week as subcutaneous injections.
After inclusion the patients will be screened. If there are no definite
sacroiliitis on X-ray, the patients will randomly and double blind be assigned
to etanercept or placebo treatment.

Subjects will be randomly assigned in a 1:1 ratio to one of the two treatment
groups
-Group 1 (n=40); 16 weeks etanercept twice weekly 25 mg subcutaneous.
-Group 2 (n=40); 16 injections with placebo twice weekly subcutaneous

The patients might have benefits of this intervention because there is a chance
that the disease activity might improve with etanercept even at a very early
stage of the disease.