Rheumatoid Arthritis Clinical Trial
Official title:
Fibrocytes in Early and Longstanding Rheumatoid Arthritis
This study will focus on a rare cell population called fibrocytes in peripheral blood and
synovial tissue in Rheumatoid Arthritis (RA). One group of patients with early RA and one
group with long-standing RA. Both groups will be followed for 6 months.
After informed and written consent a control groups is also formed: One for synovial biopsies
for patients undergoing a routine arthroscopy, where a peripheral blood sample is also taken.
The hypothesis is that fibrocytes are present in the blood and synovial tissue in RA.
Patients with early and long-standing RA have higher concentrations of fibrocytes in
peripheral blood and synovial tissue compared to a control groups. Levels of fibrocytes in
peripheral blood and synovial tissue are correlated with RA disease activity measures and
imaging findings.
The intimal lining of a synovial joint consists of unique cells called fibroblast-like
synoviocytes (FLS cells) with interspersed macrophage-like synoviocytes. In the healthy joint
macrophage-like synoviocytes are implicated in the innate immune defence and support adaptive
immunity, while FLS cells function to regulate the release of nutrients and molecules,
including hyaluronan, into the joint cavity.
Rheumatoid arthritis (RA) is a chronic systemic disease with autoimmune traits, which
primarily affects synovial joints. The intimal lining of the synovium expands and exhibits
characteristics of unregulated growth and loss of contact inhibition. The expanding synovium
degrades cartilage and erodes into the bone at the cartilage-bone interface, creating the
hallmark of RA, the joint erosion.
The RA FLS cell, has a markedly different phenotype than the healthy cell, and plays a key
role in the destructive process by the release of pro-inflammatory cytokines and matrix
destructive enzymes. FLS cells expand during the joint destructive process, however, there is
minimal mitotic activity. The origin of the expanding FLS population is therefore uncertain.
Possible explanations to this phenomenon could be decreased senescence, migration of
mesenchymal stem cells from the circulation, epithelial to mesenchymal cell-transition or
expansion of a stem cell pool in the synovium. FLS precursors could also migrate to the
synovium through pores in cortical bone, as has been demonstrated in mice with
collagen-induced arthritis. In a murine model, it has further been shown that RA FLS cells
can spread via the systemic circulation from one joint and attack previously unaffected
joints.
A possible FLS cell precursor has been identified in peripheral blood and called fibrocytes.
Fibrocytes are spindle-shaped cells that express surface receptors of both stromal and
hematopoietic cells. The fibrocytes are a rare (~0.5% of leukocytes) population of bone
marrow derived mesenchymal progenitor cells. A combination of markers that distinguish
fibrocytes from monocytes, macrophages and fibroblasts has been described. In vitro
circulating human peripheral blood mononuclear cells and monocytes (CD14+) can differentiate
into fibrocytes. Fibrocytes can differentiate in vitro along multiple mesenchymal lineages
into adipocytes, chondrocytes, myofibroblasts and osteoblasts. It is unknown which
differentiation pathway occurs in vivo or if multiple differentiation profiles can occur .
Increased numbers of circulating fibrocytes have been found in murine RA models. In a small
sample of RA patients (six patients, ten controls), peripheral blood fibrocytes had elevated
phosphorylation activation compared to controls, and cells were demonstrated in the synovium.
Here fibrocyte activation was correlated with arthritis disease activity (DAS28). In a murine
model, activated circulating fibrocytes where found to migrate to arthritis joints in the
preclinical phase of the disease, and to accumulate in the FLS cell layer of the synovium.
Adoptive transfer of circulating fibrocytes in this murine model, led to worsening of joint
disease indicating that circulating fibrocytes are involved in RA joint pathology, possibly
as a FLS-cell precursor. Further, fibrocytes have also been implicated in extra articular
manifestations of RA, e.g. pericarditis (murine model), atherosclerosis, and interstitial
lung disease.
Studies on synovial biopsies have been critical in the understanding of RA pathogenesis. A
new method of collecting synovial tissue, ultrasound-guided synovial biopsy is safe and well
tolerated by patients and reliable for collecting high quality synovial tissue from large and
small joints.
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