Rheumatoid Arthritis Clinical Trial
Official title:
Evaluation of Subcutaneous (SC) Injected Tc 99m Tilmanocept Localization in Active Rheumatoid Arthritis (RA) Subjects by SPECT and SPECT/CT Imaging
Determine the localization of Tc 99m tilmanocept by SPECT and SPECT/CT imaging in subjects with active RA and concordance with clinical symptomology.
While many types of cells, including T-cells, B-cells, dendritic cells and activated synovial
fibroblasts contribute significantly to the establishment and maintenance of the pathology of
rheumatoid arthritis (RA), (Ma et al., Noack et al., Bugatti et al., Boissier et al., Tran et
al.) macrophages play a critical role in RA (Kinne et al.). They produce most of the tumor
necrosis factor alpha (TNFα) that drives and perpetuates the inflammatory cycle in RA (Leizer
et al., Westra et al., Hamilton et al., Keffer et al., Noack et al., Bugatti et al., Boissier
et al., Tran et al., Kinne et al., Zwerina et al., Feldman et al., Schett et al.). In the
synovial sublining of a joint affected by RA, macrophages are the dominant cell type (Kraan
et al., Cutolo et al.). In the inflamed joint as a whole, macrophages in RA patients make up
at least 30%-40% of all cells (Kennedy et al.). Furthermore, macrophages participate directly
in the destruction of bone and cartilage (Ma et al.). Activated macrophage populations and
synoviocytes are the predominant cell types at the interface between pannus and cartilage and
secrete destructive proteases in abundance (Bresnihan et al.). As a result, it may not be
surprising that synovial macrophage numbers—but not the numbers of other immune cell
types—correlate with radiographically determined joint destruction in RA (Mulherin et al.,
Yanni et al.). While macrophages may play a role in other pathologies that cause joint pain
and inflammation, the degree to which macrophages are involved in the pathological process of
RA and the sheer mass or volume of macrophages that infiltrate the joints inflamed due to RA
differentiates RA from other rheumatic diseases. Therefore, detection of the density or
numbers of macrophages in inflamed joints may permit differentiation of patients with RA from
those with other causes of arthritis. In addition, it is known that the RA pathology begins
significantly before, perhaps years before, the onset of symptoms (i.e., joint pain and
inflammation) and well before the beginning of bone destruction (Deane et al., El-Gabalawy et
al.). Macrophage infiltration of synovial tissues precedes development of clinical signs of
RA in animal studies (Kraan et al.). In humans, macrophage infiltrations of synovial tissues
are present when RA patients first develop clinical symptoms (Demoruelle et al., van de Sande
et al.). Therefore, detection of the density or numbers of macrophages in inflamed joints may
facilitate more sensitive and specific identification of RA patients as soon as they present
with symptoms and early in the course of their illnesses when DMARDs are likely to be most
effective.
An interesting and important observation that has been made in many studies is that the
number of macrophages in synovial tissue, and particularly in the synovial sublining,
declines in RA patients when they are given DMARD therapy (Hamilton et al.). Furthermore, the
degree to which synovial macrophage numbers decline is correlated with the magnitude of the
DMARD (DAS28) with changes in sublining macrophage numbers as determined by biopsies and
found a significant correlation between the change in the number of macrophages and the
change in DAS28 (Pearson correlation 0.874, p < 0.01) ( Haringman et al.). The authors of
this study have confirmed these findings in two additional studies, which used slightly
different methodologies (Bresnihan et al., Bresnihan et al.). This correlation between
declining macrophage numbers and the efficacy of DMARD therapy appears to be largely
independent of the kind of DMARD therapy being investigated (Hamilton et al., Kinne et al.,
Franz et al., Kraan et al., Catrina et al., Cunnane et al., Vieira-Sousa et al.). These
findings indicate that assaying the number of macrophages in inflamed joints of patients with
RA could be used as an objective measure of the efficacy of DMARD therapy. These findings
further suggest that assaying the number of macrophages in inflamed joints of patients with
RA could be used in clinical studies as a biomarker of clinical response for potential new RA
therapeutics. The problem with current methodologies is that macrophage numbers and densities
need to be determined with synovial biopsies. This is obviously an invasive procedure that
samples only a small portion of the inflamed synovial tissue and is painful and unpleasant
for the patient. What would be preferable and likely more accurate is an imaging protocol,
such as the one proposed in this application, that can assay synovial macrophages more
completely and less invasively.
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