DC-STAMP & TRAF3: Regulators of Osteoclastogenesis and Biomarkers in PsA

Psoriatic arthritis (PsA), an inflammatory joint disease associated with psoriasis (Ps),
affects approximately 650,000 adults in the United States and is associated with increased
morbidity and mortality. Bone damage develops in half these patients within the first two
years of disease, often leaving them with impaired function and diminished quality of life.
The emergence of anti-Tumor Necrosis Factor therapies (TNFi) has dramatically improved
clinical response and slowed bone and cartilage degradation in PsA patients, however, only
50-60% of patients respond to these agents. To improve these outcomes, investigators must
address two major gaps: a limited understanding of key events that underlie pathologic bone
destruction and the absence of biomarkers to predict TNFi response and identify early TNFi
responders to facilitate optimization of therapy.

Bone damage is mediated by osteoclasts which arise from monocyte precursors in the blood.
Osteoclast Precursors (OCPs) are dramatically increased in PsA, compared to controls,
particularly in patients with bone damage on X-ray. The number of these circulation
precursor cells dropped rapidly following treatment with TNFi. OCPs may serve as response
biomarkers, but cost, time and high variability limit these assays. Osteoclast precursors
express Dendritic Cell-Specific Transmembrane Protein (DC-STAMP), which is a seven-pass
transmembrane protein required for fusion of monocytes to form osteoclasts and giant cells.
Monocyte DC-STAMP levels dropped rapidly following treatment with TNFi. TNF
receptor-associated factor 3 (TRAF3), an inhibitor of OC formation that correlates with
extracellular TNF concentrations, is elevated in OCPs from PsA patients. These markers may
predict TNFi treatment response.

The goal of this study is to examine Psoriatic Arthritis patients prior to and after TNFi
treatment, while also examining DC-STAMP and TRAF3 expression in a cross-sectional analysis
of patients on stable oral disease modifying agents (DMARDS) and in patients in low disease
activity state on TNFi therapy.

- Research Assays:

The correlation between TRAF3 and DC-STAMP expression at the RNA and protein level may be
examined for two baseline PsA patients by real-time PCR, flow cytometry and western after
Chloroquine (CQ) blockade, which prevents TRAF3 degradation. Cells isolated from human PBMC
may be sterile sorted prior to use in some in vitro assays. Sorted cells may be treated with
CQ or MG132, a proteasome inhibitor, in OC-promoting media in time course and dose-response
experiments and OCs counted to determine if DC-STAMP is degraded by the lysosome or
proteasome.

Peripheral Blood Mononucleated Cells (PBMCs) will be isolated from blood by centrifugation.
These cells may be used for flow cytometry to analyze TRAF3 and DC-STAMP expression on
monocytes along with OC quantification at baseline and/or approximately 4 months of
treatment. DC-STAMP surface expression on PBMC from PsA patients correlated with the number
of OCP in culture and the level of DC-STAMP on CD14+ monocytes declined significantly in PsA
patients following TNFi. The decline in DC-sTAMP+CD14+ cells may serve as a measure of early
response to TNFi.

Inclusion Criteria:

- All Subjects

1. Ability to provide written informed consent.

2. Subjects can be of either gender but must be at least 18 years old.

3. Subjects with PsA should fulfill CASPAR criteria

- Longitudinal

1. Patients with active PsA starting standard of care biologic treatment.

- Additional Blood Draw

1. Positive DC-STAMP signal at baseline

- Cross-Sectional 1. Patients on stable DMARDS or biologics for more than 16 weeks.

Exclusion Criteria:

1. Unable to donate blood because of poor venous access or intolerance of phlebotomy.