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

August 15, 2017 updated by: Christopher Ritchlin, University of Rochester

DC-STAMP and TRAF3: Regulators of Osteoclastogenesis and Biomarkers in Psoriatic Arthritis

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.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

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.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
68

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New York
      • Rochester, New York, United States, 14642
        • University of Rochester

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 89 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

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.

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Case-Control
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Stable PsA response to treatment
Individuals with psoriatic arthritis who are being treated standard of care with a stable DMARD or a biologic
PsA inadequate response to DMARD
Individuals with psoriatic arthritis who have had an inadequate response to a DMARD and are being treated standard of care with a biologic.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Examination of molecular mechanisms underlying DC-STAMP and TRAF3 mediated osteoclastogenesis
Time Frame: week 0 to week 16
Investigators will analyze TRAF3 and DC-STAMP expression in monocytes from PsA patients cross-sectionally by flow cytometry. Disease Activity Score 66/68 (DAS66/68), TRAF3 levels and the change in DC-STAMP+CD14+ will be observed to see if they correlate with standard of care treatment.
week 0 to week 16

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Assessment of DC-STAMP and TRAF3 as biologic predictor and treatment response markers in PsA
Time Frame: week 0 to week 16
Investigators will analyze TRAF3 and DC-STAMP expression in monocytes from PsA patients longitudinally by flow cytometry. Disease Activity Score 66/68 (DAS66/68), TRAF3 levels and the change in DC-STAMP+CD14+ will be observed to see if they correlate with standard of care treatment.
week 0 to week 16

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Rochester

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
April 13, 2015

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 28, 2016

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 28, 2016

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
April 7, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 9, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 10, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
August 18, 2017

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
August 15, 2017

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
August 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • RSRB 53086

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Yes

IPD Plan Description

Information of any type may be shared with researchers at other institutions. Subjects will be made aware of this in the informed consent form.

IPD Sharing Time Frame

Once a subject signs the consent form to allow for sharing, If any samples remain after all tests are completed, the samples will be stored for future research indefinitely or until the subject cancels consent to share.

IPD Sharing Access Criteria

Only investigators that the study team collaborates with will have access to samples. Data will not include any information that is identifying.

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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