DC-STAMP & TRAF3: Regulators of Osteoclastogenesis and Biomarkers in PsA
Condition: Psoriatic Arthritis
MeSH terms: Arthritis; Arthritis, Psoriatic
Study type: Observational

Summary: 
      Biologics such as anti-Tumor Necrosis Factor or TNF inhibitor (TNFi) for treatment of
      Psoriatic Arthritis (PsA) has greatly reduced bone damage. This collaborative study will
      provide insights into key mechanisms that underlie inflammatory arthritis and bone damage in
      psoriatic joints and will catalyze biomarker discovery, identifying early biologic responders
      to facilitate optimization of therapy.
    

Detailed description: 
      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 standard
      of care biologic treatment such as TNFi, 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.
    

Observational model: Case-Control
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Male and female subjects that are 18 years old and older. Due to the demographic
        distribution of the disease we expect all or nearly all subjects to be caucasian, however
        no subjects will be excluded based on race or ethnic origin.
      
Biospecimen description: 
      Peripheral blood samples that remain after study assays are completed may be stored for
      future non-genetic research.
    
Keywords: Psoriatic Arthritis