Session Information
Session Title: Spondyloarthropathies and Psoriatic Arthritis: Pathogenesis, Etiology, Animal Models I
Session Type: Abstract Submissions (ACR)
Background/Purpose:
Ankylosing Spondylitis (AS) is characterized by inflammation of the spine and entheses followed by formation of syndesmophytes.
Wnt pathway is a regulator of bone and cartilage remodeling; modulated by several biomarkers like Dickkopf (DKK-types 1, 2, 3 & 4), sclerostin, etc.
DKK1 is an inhibitor of Wnt. TNF-alpha inhibits bone formation by inducing Dkk-1.
AS patients display either low levels of functional DKK1 (DKK1 that binds to LRP5/6- Low-density lipoprotein receptor related protein) or high levels of total DKK1 indicating that it is dysfunctional.
Maksymowych et al, showed that new syndesmophytes developed more frequently in vertebral corners with inflammation on baseline MRI; and more so where inflammation had resolved after 2 years of anti-TNF therapy.
We examined the relationship between inflammation, bone formation and bone biomarkers in AS patients not on anti-TNF therapy. The anthrax toxin binding protein (CMG2) is a decoy receptor for DKK; which has been found to be associated with AS; we examined its association with DKK.
Methods:
We recruited 35 patients with spondyloarthritis, (34 fulfilling New York criteria & 1 fulfilling ASAS criteria for axial spondyloarthritis) from a preexisting cohort, Prospective Study on Ankylosing spondylitis Severity (PSOAS) and from the office of the principal investigator.
During the study visit, metrology measurements were done and BASMI calculated. Bath AS Disease Activity and Functional Indices (BASDAI, BASFI) were also obtained. Blood samples were examined for the following: ESR, CRP, Vitamin D, PTH, DKK, LRPDKK, OPG (Osteoprotegrin), sclerostin, antiDKK, SFRP 3, CMG2DKK, and CMG2LRP. X-rays of the pelvis and the entire spine that were available for 35 and 28 patients respectively were scored for the sacroilitis grade (SI grade) and the modified Stokes Ankylosing Spondylitis Spine Score (mSASSS). Statistical analysis was performed using Spearman correlation coefficient and Student t-test.
Results:
1. Significant correlation between DKK, LRPDKK& CMGDKK as well as between mSASSS, SI grade and BASMI. (Table 1).
2. LRPDKK increases with inflammation in AS. Bone formation as indicated by mSASSS trended higher in patients with higher levels of inflammation.
3. Patients with low CRP when separated based on high or low mSASSS, showed that high mSASSS correlated negatively with DKK and LRPDKK.
Table 1
|
Variable |
N |
Mean |
Std. Dev |
Median |
Minimum |
Maximum |
Correlation |
P-value |
|
Markers of inflammation and function |
||||||||
|
CRP |
32 |
1.99 |
4.64 |
0.57 |
0.03 |
22.9 |
ESR 0.83 BASDAI 0.43 |
<.0001 0.0119 |
|
ESR |
33 |
23.42 |
23.42 |
14.00 |
1.00 |
98.00 |
|
|
|
BASDAI |
34 |
4.10 |
4.49 |
3.08 |
0.00 |
24.9 |
BASFI 0.55 |
0.0008 |
|
BASFI |
34 |
23.70 |
25.52 |
14.95 |
0.00 |
99.00 |
|
|
|
Bone biomarkers associated with bone formation |
||||||||
|
DKK |
35 |
4.03 |
2.93 |
3.47 |
0.39 |
15.52 |
LRPDKK 0.87 CMG2DKK 0.51 |
<.0001 0.0035 |
|
LRPDKK |
30 |
2.92 |
1.52 |
2.91 |
0.22 |
6.39 |
CMG2DKK 0.55 |
0.0015 |
|
CMG2DKK |
30 |
0.70 |
0.57 |
0.39 |
0.39 |
2.15 |
|
|
|
Radiologic and Mobility measurements |
||||||||
|
mSASSS |
28 |
18.54 |
22.47 |
6.5 |
0.00 |
72.00 |
SIJ 0.75 BASMI 0.80 |
<0.0001 <0.0001 |
|
SIJ Grade |
34 |
3.29 |
1.00 |
4.00 |
0.00 |
4.00 |
BASMI 0.52 |
0.009 |
|
BASMI |
25 |
3.75 |
1.64 |
4.00 |
0.6 |
6.8 |
|
|
|
Low versus High CRP groups |
||||||||
|
LRPDKK(low CRP) |
15 |
– |
– |
1.98 |
0.23 |
4.9 |
– |
0.0009 |
|
LRPDKK(high CRP) |
12 |
– |
– |
4.04 |
1.38 |
6.39 |
– |
|
|
mSASSS(low CRP) |
16 |
– |
– |
5.5 |
0 |
62 |
– |
0.082 |
|
mSASSS(high CRP) |
11 |
– |
– |
24 |
0 |
72 |
– |
|
|
DKK and LRPDKK levels influencing mSASSS in low CRP group |
||||||||
|
DKK(low CRP,low mSASSS) |
12 |
– |
– |
3.36 |
2 |
7.41 |
– |
0.013 |
|
DKK(Low CRP, high mSASSS) |
4 |
– |
– |
0.78 |
0.39 |
3.09 |
– |
|
|
LRPDKK(low CRP, low mSASSS) |
10 |
– |
– |
2.32 |
1.56 |
4.91 |
– |
0.008 |
|
LRPDkk(low CRP,high mSASSS) |
4 |
– |
– |
1.01 |
0.23 |
1.85 |
– |
|
Conclusion:
Our pilot study suggests that inflammation and low levels of functional DKK are associated with increased bone formation in anti-TNF naïve AS patients. Functional DKK levels increases with active inflammation. However, with low levels of inflammation, functional DKK correlated negatively with AS x-ray changes. A positive correlation exists between the binding of LRPDKK to a decoy receptor CMG2 and LRPDKK levels in these patients.
Funded by a grant from the Spondylitis Association of America
Disclosure:
R. Gulati,
None;
M. Corr,
None;
M. H. Weisman,
None;
D. Hallegua,
None.
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