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

Psoriatic Arthritis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01123265
• Other study ID #: RSRB - 32368
• Status: Completed
• Phase: Phase 4
• First received: May 11, 2010
• Last updated: September 17, 2015
• Start date: June 2010
• Est. completion date: June 2014

Study information

• Verified date: September 2015
• Source: University of Rochester
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Observational

Clinical Trial 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.

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:

1. DC-STAMP+ CD3+ T cells belong to the Th17 subset which facilitates OC generation;

2. DC-STAMP is a marker of disease severity in PsA;

3. 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22
• Est. completion date: June 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Subject must be >18 years old

2. Subject must have >3 tender and swollen joints

3. Subject must have must have a target lesion of greater than 3 cm in diameter

4. Subjects who meet the the ClASsification of Psoriatic ARthritis (CASPAR) criteria for PsA

5. Subjects must have a DC-STAMP pattern III or IV

Exclusion Criteria:

1. Subjects with active inflammatory synovitis, dactylitis, enthesitis, osteoarthritis, axial disease, Subjects with a SLE, Sjogren's syndrome, scleroderma or inflammatory muscle disease

2. Subjects with an active malignancy

3. 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)

4. Subjects who have been off DMARDs or biologics for less than 3 months

5. Subjects judged ineligible at the discretion of the PI

6. Subjects with a history of crystalline arthritis (gout, pseudogout)

7. Subject pregnancy or breast feeding

8. History of recurrent infections - AIM 3 Specific

9. Demyelinating disorders - AIM 3 Specific

10. Prior non-responsiveness to TNFi - AIM 3 Specific

11. Subjects who have a BMI >30 - AIM 3 Specific MTX arm

12. Subjects who have a history of type II diabetes - AIM 3 Specific MTX arm

13. Subjects with a history of substance abuse including alcohol - AIM 3 Specific MTX arm

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Arthritis
• Arthritis, Psoriatic
• Psoriatic Arthritis

Intervention

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

Locations

Country	Name	City	State
United States	University of Rochester	Rochester	New York

Sponsors (2)

Lead Sponsor	Collaborator
University of Rochester	National Psoriasis Foundation

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Analysis of T cell subset and dendritic cell (DC) subset for DC-STAMP expression	Determine whether DC-STAMP+ cells belong to the Th17 subset and also analyze the DC subsets for DC-STAMP expression.	Week 0 (Baseline)	No
Primary	Analysis of T cell subset and DC subset for DC-STAMP expression	Determine whether DC-STAMP+ cells belong to the Th17 subset and also analyze the DC subsets for DC-STAMP expression.	Week 16	No
Primary	DC-STAMP as a marker of disease severity in PsA	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.	Week 0 (Baseline)	No
Primary	DC-STAMP as a marker of disease severity in PsA	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.	Week 16	No
Primary	DC-STAMP as a biomarker of treatment response in PsA	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.	Week 0 (Baseline)	No
Primary	DC-STAMP as a biomarker of treatment response in PsA	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.	Week 16	No