Synoviomics II: Advanced genomics intitiative in different phases of arthritis

Heterogeneity
Although RA is thought of as an autoimmune disease, its etiology is unknown.
Different stimuli, including exogenous infectious agents and endogenous
connective tissue proteins like cartilage components have been suggested as
possible primary causes that activate the immune response. There is growing
evidence that patients with RA, as defined by the American College of
Rheumatology Classification Criteria, represent a highly heterogeneous group.
This heterogeneity of RA is indicated by notable variability in clinical
presentation, the existence of erosive versus non-erosive disease, and the
presence of distinct autoantibody specificities, such as rheumatoid factor and
anticyclic citrullinated peptide antibodies in the serum.
Window of opportunity
Disease heterogeneity is also apparent in histological features of the synovium
and in a marked variation in gene expression profiles, allowing identification
of molecularly distinct forms of RA synovium. Consistent with this finding is
the wide variation in responsiveness to treatment in RA. The relative
contribution of these probable different disease mechanisms in RA may vary
between patients and in different stages of the disease. This has been posted
as the reason for the existence of a so-called therapeutic *window of
opportunity phase* of the disease, which means that applying the right
therapeutic intervention during the right phase of the disease will lead to a
better control of the disease activity and consequently to less radiographic
damage. The pathogenetic mechanisms underlying these differences found in
patient characteristics and reactions to treatment are subject of extensive
research.
One hypothesis is that the features of the inflamed synovial tissue change over
time. Transformation of resident fibroblasts into invasive cells, intruding
into the cartilage and bone, could be one of the explanations that patients
with longer disease duration are more likely to fail on therapy. Other factors
include the release of crystals from degraded bone and cartilage with secondary
pro-inflammatory effects. It is likely that these phenomena are not limited to
RA and they may occur in other chronic arthritides as well
Disease activity and new therapeutic targets
As a consequence of the above mentioned hypothesis, different stages of the
disease could require different therapeutic regimens. Identification of new
therapeutic targets in relationship to the phase of the disease and disease
activity might lead to novel strategies to improve treatment of RA.
Pathogenesis of inflammatory joint diseases other than RA
Furthermore, the pathogenesis of other inflammatory joint diseases, such as
different forms of seronegative spondyloarthritis like psoraitic arthirits,
ankylosing spondylitis and reactive arthritis, as well as crystal deposition
disease, and inflammatory osteoarthritis, has not been elucidated. Since the
synovial tissue is the target tissue of all inflammatory joint diseases,
studying the specific features of this tissue in different stages of the
disease process, using different innovative techniques, will contribute to an
understanding of the processes underlying these diseases. This could lead to
the identification of novel therapeutic targets for these diseases. Comparison
with RA synovial tissue will allow identification of variables associated with
persistence and destruction.

- To investigate different pathogenetic mechanisms underlying the clinical
syndrome termed RA
- To investigate changes in the synovial tissue in relationship to the duration
of disease
- To identify new therapeutic targets in the synovial tissue in different
stages of the disease
- To study the different pathogenetic pathways in the synovial tissue leading
to the various inflammatory joint diseases
- To investigate new diagnostic markers in synovial tissue using molecular
signatures of different inflammatory joint diseases

Inclusion criteria:
Patients with inflammatory joint disease and active inflammation of at least a
knee or ankle joint

Clinical evaluation and demographics:
Recording of:
- Demographic data - date of birth, sex, and race.
- Disease duration.
- Disease activity parameters (Visual analog scale of disease activity and
pain, 68 joint score, ESR, CRP)
- Present use of NSAIDs, corticosteroids, DMARDs, biologicals or other
experimental drugs.
Joint destruction will be evaluated by conventional X-ray of the joint.

Collection of material:
During mini-arthroscopy synovial tissue will be collected through a biopsy
technique.
Synovial biopsies will be collected and processed using a standard protocol for
formalin fixation, to allow standard histological evaluation, and samples will
be frozen en bloc for immunohistochemistry, PCR, micro-array and protein
expression analysis. Samples will be collected for fibroblast like synoviocyte
cell culture using a standard protocol.

Bloodsampling: blood (14 ml) will be collected to classify the patients.
Rheumatoid factor, anti-CCP antibodies, CRP, and ESR will be determined. If
informed consent is given for genetic studies, an extra blood sample of 7 ml
will be drawn from the patient.

A mini-(or needle) arthroscopy perfomed under local aneasthesia at the
outpatient clinic. Afterwards the patients are capable of walking. 24 hours of
relative rest will be advised.

There is a small change of a joint inflammation (less then 3 percent).