1. Inderjeet Verma (Senior Research Fellow)
Endothelial progenitor cell biology in psoriatic arthritis patients: from biomarker to therapeutic agent
Inderjeet Verma (Senior Research Fellow)
Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India.
Cardio-Rheuma & Healing Touch City Clinic, Chandigarh

2. Disclosures…
This study was supported by University Grant Commission (UGC), New Delhi, F.No /2007 (SA-1)
No other relevant financial involvement with any other organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the presentation apart from those disclosed.
No assistance was utilized in the production of this presentation

3. Study Background….. Arthritis Rheum. 2007;57)6):1074-80.
Psoriatic arthritis (PsA) is an immune-mediated inflammatory arthritis associated with psoriasis. Annual incidence of PsA ranges from 0.1 to 23.1 per 100,000.
Int J Rheum Article ID 71432
Cardiovascular disease is one of the leading causes of death in patients with PsA.
Arthritis Rheum. 2007;57)6):
Chronic immune-mediated inflammation plays a key role in the pathogenesis of atherosclerosis in PsA, acting independently and/or synergistically with the conventional risk factors.
Semin Arthritis Rheum. 2004;34:
Endothelial progenitor cells (EPCs) are bone-marrow derived stem cells that contribute to vascular homeostasis and may serve as a circulating pool of cells to improve endothelial dysfunction.
Annu Rev Med. 2005;56:

4. Study Background….new possibilities
EPCs: better predictor of endothelial dysfunction than conventional risk factors; predict occurrence of CV events & cardiovascular death.
Arterio Throm Vas Biol 2006;26:
Depletion of EPC population have been shown in RA, recently in AS and other RDs.
Arthritis Rheum. 2009; 60:3168–79
Int J Rheum Dis doi: / X.12487
EPCs contribute to the enhanced CV risk & predict the occurrence of CV events & cardiovascular death.
Previously EPC population has been assessed in a heterogeneous population of with equivocal results in psoriatic arthritis (PsA) patients with confounding factors.
Rheumatol Int. 2009;29: .

5. Potential mechanisms involved in reduced EPC levels in rheumatic disease
Westerweel PE and Verhaar MC (2009) Endothelial progenitor cell dysfunction in rheumatic disease Nat Rev Rheumatol doi: /nrrheum

6. Study Objective….
The aim of this study was to investigate EPC population in PsA patients in the absence of traditional cardiovascular risk factors.
Its relationship with surrogate of atherosclerosis and clinical parameters of disease activity as well as measures of inflammatory markers.

7. Flow Mediated Dilatation (FMD) Carotid intimal medial thickness (CIMT)
STUDY DESIGN
Screening
Exclusion criteria
Inclusion criteria
Cardiovascular/cerebrovascular disorders
Diabetes mellitus, thyroid disorders,
malignancy, Renal or liver insufficiency,
Pregnant or breastfeeding women
Previous use of TNFi, ACE inhibitors, ARBs
Statin, PPAR agonists, steroids, estrogen
or EPO
Patients ages ≥18 years with PsA
classified according to CASPAR criteria
Normotensive.
Non-smokers.
20 healthy controls were recruited from
the clinic staff. .
Psoriatic arthritis
n=22
Healthy controls
n=20
Assessment
Assessment of inflammatory markers:
ESR & CRP
Assessment of Disease Activity:
DAS-28 and DAPSA
Proinflammatory Cytokines:
TNF-α, IL-6 & IL-1)
EPC (CD34+/CD133) by Flow Cytometry
(canto II, BD Bio Sciences)
Flow Mediated Dilatation (FMD)
Carotid intimal medial thickness (CIMT) .

8. Table 1. Demographic and laboratory characteristics of the participants
Variable
Psoriatic Arthritis
Healthy Controls
P value n 22 20
Age (years)
45.1 ± 13.8
43.9 ± 12.6
0.49
Sex (men/women)
13/9
12/8
0.33
BMI (kg/m2)
26.3 ± 4.76
25.2 ± 3.2
0.27
Smoking (number) -
Systolic BP (mm Hg)
126.2 ± 9.42
123.0 ± 12.0
0.36
Diastolic BP (mm Hg)
79.8 ± 8.6
78.3 ± 8.0
0.57
Disease Duration (years)
7.5 ± 4.6
HbA1c (%)
5.28 ±1.6
5.08 ± 0.6
0.40
Total cholesterol (mg/dl)
180.3 ± 19.90
174.9 ± 16.34
HDL cholesterol (mg/dl)
43.0 ± 3.87
47.26 ± 5.59
0.047*
LDL cholesterol (mg/dl)
97.21 ± 20.04
88.68 ± 21.96
0.171
Triglycerides (mg/dl)
± 19.15
± 12.18
0.141
Serum creatinine (μmol/l)
0.91±13
0.86±10
0.527
Values are mean ± SD; BMI: body mass index, HDL: high-density lipoprotein, LDL: low-density lipoprotein, DAS: disease activity score, DAPSA: disease activity index for psoriatic arthritis. ESR: erythrocyte sedimentation rate, CRP: C-reactive protein. *P-value <0.05.

9. Table 2. Clinical, inflammatory and vascular measures of the study subjects
Variable
Psoriatic Arthritis
Healthy Controls
P value n 22 20
DAS-28
4.03 ± 0.74 -
DAPSA
27.2 ± 17.7
ESR (mm 1st hr)
24.64 ± 6.78
16.68 ± 4.54
0.001*
CRP (mg/dl)
10.79 ± 7.96
3.93 ± 2.10
0.003*
TNF-α (pg/ml)
8.82 ± 4.07
4.07 ± 0.85
IL-6 (pg/ml)
8.77 ± 3.67
4.2 ± 2.83
0.004*
IL-1 (pg/ml)
172.9 ± 78.2
90.0 ± 18.9
EPC%
0.028 ± 0.009
0.047 ± 0.006
<0.001*
FMD%
7.43 ± 2.12
10.52 ± 0.77
cIMT (mm)
0.65 ± 0.17
0.56 ± 0.09
0.068
Values are mean ± SD; EPC: endothelail progenitor cells, FMD: flow mediated dilatation, cIMT: carotid intima media thickness, TNF-α: tumor necrosis factor-a, IL-6: interleukin-6 and IL-1: : interleukin-1. *P-value <0.05.

10. Figure. 1 Fluorescence-activated cell sorting (FACS) analysis without the use of a viability marker: the first region (P1) sorts the immature mononuclear cells, the second (P2) identifies CD45 positive cells. The third (P3) identifies CD34 positive cells and the forth (P4) identifies CD133 positive cells. The fifth dotblot gates in quadrant 2 (Q2), identifies the cells positive for CD34 and CD133. Percentage of EPC cells was calculated as double positive cells on dotblot of CD34+ CD133+

11. Table 3. Correlation analyses between EPC population and disease activity, inflammatory measures and surrogates of vascular function
EPC Population
Correlation Coefficient
pValue
AGE
-0.315
0.186
Disease duration
-0.166
0.489
BMI
-0.331
0.175
ESR
-0.245
0.325
CRP
-0.657
0.002*
DAS-28
-0.633
0.004*
DAPSA
-0.535
0.021*
TNF- α
-0.586
0.01*
IL-6
-0.641
0.003*
IL-1
-0.451
0.058
FMD
0.669
CIMT
0.214
0.388
BMI: body mass index, ESR: erythrocyte sedimentation rate, CRP: C-reactive protein, DAS: disease activity score, DAPSA: disease activity index for psoriatic arthritis. FMD: flow mediated dilatation, cIMT: carotid intima media thickness, TNF-α: tumor necrosis factor-a, IL-6: interleukin-6 and IL-1: interleukin-1. *P-value <0.05

12. Fig. 3 Inverse correlation between EPC population and inflammatory measures (CRP & TNF-α)

13. Fig. 3. EPC % showed significant inverse correlation with disesae activity (DAPSA) and positive correlation with FMD% score

14. First study to report depleted EPCs in PsA. EPCs correlate with:
Disease activity
Inflammatory measures (CRP, TNF-α and IL-6)
FMD%
Suggesting the pivotal role of inflammation in depletion of EPC population.
EPC depletion in turn appears to contribute to the enhanced CV risk seen in PsA.

15. Study Implication….
This study opens many domains of investigation of EPC biology in PsA. The potential role of these cells as surrogate biomarkers of endothelial dysfunction/injury or as potential pathogenic players in PsA should be further investigated.
EPCs would possibly also serve as a therapeutic target for preventing cardiovascular risk associated with endothelial dysfunction in PsA.

16. Thank You
Thank You