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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Psoriatic Arthritis

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Anti-TNF


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) | 
| 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 | 
| 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) | 
| 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 | 
| 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) | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PsA, methotrexate, Anti-TNF, TNF, DC-Stamp