National Psoriasis Foundation - Dendritic Cell-Specific Transmembrane Protein (DC-Stamp) Biomarker Study
Status: | Completed |
---|---|
Conditions: | Arthritis, Psoriasis |
Therapuetic Areas: | Dermatology / Plastic Surgery, Rheumatology |
Healthy: | No |
Age Range: | 18 - Any |
Updated: | 4/21/2016 |
Start Date: | June 2010 |
End Date: | June 2014 |
Dendritic Cell-Specific Transmembrane Protein (DC-STAMP) as a Severity and Response Biomarker in Psoriatic Arthritis
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.
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.
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.
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.
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
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