National Psoriasis Foundation - Dendritic Cell-Specific Transmembrane Protein (DC-Stamp) Biomarker Study

Sponsor

University of Rochester (Other)

Overall Status

Completed

CT.gov ID

NCT01123265

Collaborator

National Psoriasis Foundation (Other)

Enrollment

Location

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether DC-STAMP, a protein on the surface of osteoclast precursors (OCPs), can be used as a biologic marker in Psoriatic Arthritis (PsA). With this marker the investigators hope to learn more about how OCPs develop as well as find out if DC-STAMP predicts PsA severity and how well treatment works in PsA.

Condition or Disease	Intervention/Treatment	Phase
Psoriatic Arthritis	Drug: Methotrexate Drug: Anti-TNF

Detailed Description

Psoriatic Arthritis (PsA), a phenotypically heterogeneous disorder, is characterized by joint damage observed in over half of the patients with early disease. While anti-tumor necrosis factor (TNF) agents have greatly improved signs and symptoms and lessened joint damage, the fact that only a fraction of patients achieve complete remission underscores the tremendous unmet need for this population. To date, a biomarker that can stratify patients by severity and can serve as a leading indicator of treatment response has not been identified.

Our laboratory demonstrated that circulating osteoclast precursors (OCP) are elevated in PsA patients. OCP decline rapidly following anti-TNF therapy and levels are higher in subjects with erosive arthritis compared to those with no x-ray changes. The OCP are derived from CD14+ monocytes and the assay entails culture techniques that are costly, expensive and labor intensive. We developed an antibody (1A2) to Dendritic Cell Specific Transmembrane Protein (DC-STAMP), a potential marker of the OCP population, for analysis by flow cytometry. We found that: 1) the level of monocyte DC-STAMP expression correlated with in vitro osteoclast formation; 2) DC-STAMP expression is significantly elevated in PBMC from PsA subjects compared to controls; 3) TNF dramatically upregulated the expression of DC-STAMP in vitro; 4) DC-STAMP surface expression declined following anti-TNF therapy; 5) subsets of CD3+ cells also express DC-STAMP on the cell membrane. Based on these preliminary data, three hypotheses are proposed:

DC-STAMP+ CD3+ T cells belong to the Th17 subset which facilitates OC generation;
DC-STAMP is a marker of disease severity in PsA;
DC-STAMP is a biomarker of treatment response in PsA.

We propose three Specific Aims to test these hypotheses.

Aim 1 To examine whether DC-STAMP+CD3+ cells belong to the Th17 cell subset, PBMC will be stained with Th17-specific antibodies in PsA subjects with elevated DC-STAMP expression. We will also examine the role of T cells in osteoclastogenesis directly by co-culture experiments and we will use monocyte cultures without added lymphocytes as controls. The expression of DC-STAMP on circulating dendritic cells will be examined ex vivo with 11-color flow cytometry.

Aim 2 To determine if increased DC-STAMP expression is associated with more severe features of PsA, DC-STAMP expression in 40 PsA subjects will be determined and correlated with clinical variables of arthritis and skin disease, CRP and x-ray damage.

Aim 3 To examine if DC-STAMP is a response marker to anti-TNF treatment, we will recruit 20 PsA patients in Aim 2 with elevated DC-STAMP expression and divide them into 2 groups. Ten subjects will receive methotrexate, and ten will receive anti-TNF therapy. The correlation between DC-STAMP variables (percentage of 1A2+ divided by 1A2 - cells X 100) and the variables detailed in Aim 2 will be analyzed in these 2 treatment groups at 2 different time points.

Study Design

Study Type:

Observational

Actual Enrollment :

22 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) as a Severity and Response Biomarker in Psoriatic Arthritis

Study Start Date :

Jun 1, 2010

Actual Primary Completion Date :

Jun 1, 2014

Actual Study Completion Date :

Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Anti-TNF	Drug: Anti-TNF Anti-TNF to be administered per standard of care within the practice.
Methotrexate	Drug: Methotrexate Subjects will start Methotrexate which will be escalated from 7.5 mg weekly to 15 mg/weekly over a 3 week period.

Arm

Intervention/Treatment

Anti-TNF

Drug: Anti-TNF

Anti-TNF to be administered per standard of care within the practice.

Methotrexate

Drug: Methotrexate

Subjects will start Methotrexate which will be escalated from 7.5 mg weekly to 15 mg/weekly over a 3 week period.

Outcome Measures

Primary Outcome Measures

Analysis of T cell subset and dendritic cell (DC) subset for DC-STAMP expression [Week 0 (Baseline)]
Determine whether DC-STAMP+ cells belong to the Th17 subset and also analyze the DC subsets for DC-STAMP expression.
Analysis of T cell subset and DC subset for DC-STAMP expression [Week 16]
Determine whether DC-STAMP+ cells belong to the Th17 subset and also analyze the DC subsets for DC-STAMP expression.
DC-STAMP as a marker of disease severity in PsA [Week 0 (Baseline)]
Baseline measurement of DC-STAMP expression will be collected in order to assist in determining whether it is associated with more severe features of PsA. DC-STAMP expression will be correlated with clinical variables of arthritis and skin disease, CRP and x-ray damage.
DC-STAMP as a marker of disease severity in PsA [Week 16]
Measurement of DC-STAMP expression will be collected in order to assist in determining whether it is associated with more severe features of PsA. DC-STAMP expression will be correlated with clinical variables of arthritis and skin disease, CRP and x-ray damage.
DC-STAMP as a biomarker of treatment response in PsA [Week 0 (Baseline)]
A baseline measurement of DC-STAMP as a response marker to treatment will be collected. Ten subjects will receive methotrexate and ten will receive anti-TNF therapy. The correlation between DC-STAMP variables (percentage of 1A2+ divided by 1A2 - cells X 100) and the variables detailed in Aim 2 will be analyzed in these 2 treatment groups at 2 different time points.
DC-STAMP as a biomarker of treatment response in PsA [Week 16]
A measurement of DC-STAMP as a response marker to treatment will be collected. Ten subjects received methotrexate and ten received anti-TNF therapy. The correlation between DC-STAMP variables (percentage of 1A2+ divided by 1A2 - cells X 100) and the variables detailed in Aim 2 will be analyzed in these 2 treatment groups at 2 different time points.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Subject must be >18 years old
Subject must have >3 tender and swollen joints
Subject must have must have a target lesion of greater than 3 cm in diameter
Subjects who meet the the ClASsification of Psoriatic ARthritis (CASPAR) criteria for PsA
Subjects must have a DC-STAMP pattern III or IV

Exclusion Criteria:

Subjects with active inflammatory synovitis, dactylitis, enthesitis, osteoarthritis, axial disease, Subjects with a SLE, Sjogren's syndrome, scleroderma or inflammatory muscle disease
Subjects with an active malignancy
Subjects currently on biologic agents (anti-TNF agents, anti-T or B cells agents) and/or disease-modifying antirheumatic drugs (DMARDs) (methotrexate, leflunomide, hydroxychloroquine, azulfidine, cyclosporine, azathioprine)
Subjects who have been off DMARDs or biologics for less than 3 months
Subjects judged ineligible at the discretion of the PI
Subjects with a history of crystalline arthritis (gout, pseudogout)
Subject pregnancy or breast feeding
History of recurrent infections - AIM 3 Specific
Demyelinating disorders - AIM 3 Specific
Prior non-responsiveness to TNFi - AIM 3 Specific
Subjects who have a BMI >30 - AIM 3 Specific MTX arm
Subjects who have a history of type II diabetes - AIM 3 Specific MTX arm
Subjects with a history of substance abuse including alcohol - AIM 3 Specific MTX arm