national psoriasis foundation - dendritic cell-specific transmembrane protein (dc-stamp) biomarker study

Conditions: Psoriatic Arthritis

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.

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.

Eligibility criteria:
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

Keywords: psa methotrexate anti-tnf tnf dc-stamp