Download Late synovial enhancement detects effects of intra

Late synovial enhancement detects effects of intraarticular steroids on synovitis better than synovial volume
A. D. Gait1, E. J. Marjanovic1,2, M. J. Parkes2,R. Hodgson1, T. F. Cootes1,
T. W. O'Neill2,5, C. E. Hutchinson3, D. T. Felson2,4,5
1Department of
Imaging Science and Biomedical Engineering (ISBE), Univ. of Manchester, Manchester, UNITED KINGDOM.
in Osteoarthritis Manchester (ROAM), Arthritis Research UK Epidemiology Unit, Univ. of Manchester, Manchester, UNITED KINGDOM.
School, Univ. of Warwick, Coventry, UNITED KINGDOM.
4Clinical Epidemiology Unit, Boston Univ. School of Medicine, Boston, MA, USA.
5NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UNITED
KINGDOM.
2Research
3Warwick Medical
BACKGROUND
 In knee OA, knee pain decreases after intra-articular steroid
treatment but the optimal way to assess an effect of this treatment
on synovium is unknown.
 On contrast enhanced MRI, static synovial volume can be quantified
as can the dynamic rate of enhancement of synovium at different
times after contrast injection.
 The best way to evaluate synovium after treatment would maximize
the correlation between synovial change and pain change.
AIM
 In persons undergoing intra-articular steroid injections of the knee,
do changes in dynamic parameters of synovial enhancement
correlate better with reduction in knee pain than changes in static
synovial volumes?
METHODS
Subjects with symptomatic knee OA (ACR criteria)
Design: Open Label Clinical Trial (‘TASK’) ISRCTN07329370, in
which subjects had 2 contrast enhanced MRI’s, one before intraarticular steroid injection and one 5-15 days afterward.
Intervention: Intra-articular depomedrone 80mg
Pain Assessments:
 VAS score - pain on nominated activity (VASNA): 0 (no pain) to 10
 Assessments at baseline and 5-15 days post injection
FIGURE 2: EXAMPLES OF RESULTS OF IMAGE ANALYSIS FOLLOWING
MANUAL SEGMENTATION OF SYNOVIAL TISSUE LAYER (CARTILAGE: GREEN;
SYNOVIAL FLUID: BLUE; SYNOVIAL TISSUE: RED)
Baseline, TA024
Baseline, TA009
Visit 2, TA024
Visit 2, TA009
 We overlaid the manually segmented regions of synovial tissue onto
these parameter images (via image registration) and calculated the
median value.
STATISTICAL ANALYSIS
 Assessment of the change in static volume V and dynamic
parameters from baseline to post-injection visit was done by
calculation of a Pearson coefficient correlation matrix.
 Assessment of linear regression measures between each of these
parameters and each pain scale was then performed.
RESULTS
 For the 72 patients (41.7% female, mean age 64.3), every dynamic
parameter showed a reduction in response to treatment between
baseline and follow-up (Table 1).
TABLE 1: STANDARDISED RESPONSE MEANS FOR CHANGE IN EACH
PARAMETER IN THE STUDY, FOLLOWING TREATMENT
IMAGING
Variable
MRI Scan: 3T Philips MRI, Gadolinium-enhanced sequences
 (~7 minutes, axial, 18 images at ~22-second intervals) TR 5.3 ms,
TE 1.463 ms, FoV 14cmx14cm, Slice thickness 3mm (used for
dynamic data)
 (sagittal), taken ~8 minutes after enhancement: TR 500ms, TE
17ms, FoV 15.9cm x 15.9cm, Slice thickness 3mm (used for static
volumes) (Figure 1)
Variable description
SRM (mean change / SD(mean change))
Permeability parameter in
Tofts equation
Fractional volume of extrave
cellular space
Fractional volume of plasma
vp
space
Ktrans
V
FIGURE 1: POST GD-ENHANCED MRI SHOWING SYNOVITIS CHANGE
-0.62
-0.46
-0.23
(Static) volume
-0.41
V×s
(Static) volume * synovial
fraction
-0.37
Gmax
Maximum gradient
-0.63
Sl Late relative enhancement
-0.76
Maximum relative
enhancement
Visual analogue scale for
Pain on nominated activity VAS
pain, completed by patient
Sr
Baseline visit
Post-injection visit
IMAGE ANALYSIS: MANUAL SEGMENTATION
 Manual segmentation of the synovial tissue layer (including fluid and
possibly cartilage) was performed on the post contrast knee image
by a single observer (ICC=0.94).
 We excluded cartilage within the segmented space by thresholding
in a registered sagittal scan (3DWATSc: TR 20ms, TE 7.7ms, FoV
15cmx15cm, slice thickness 1.5mm).
We calculated the proportion s of synovial tissue in every voxel
using s=(S-mf)/(ms-mf) truncated to [0,1], where S is the voxel
intensity and mf, ms are the means of the intensity distributions of
fluid and synovial tissue volume (Figure 2).
 Sl, Sr and Gmax all correlated with K
trans
-0.73
-1.17
(Table 2).
TABLE 2: PEARSON CORRELATION COEFFICIENT MATRIX
Correlations
Ktrans
Ktrans
1.00
ve
vp
ve
0.71
1.00
vp
-0.13
-0.10
1.00
V
V×s
G max
Sl
Sr
V
0.15
0.10
0.04
1.00
V×s
0.11
0.08
0.13
0.94
1.00
Gmax
0.70
0.34
0.21
0.09
0.03
1.00
Sl
0.78
0.66
-0.04
0.23
0.18
0.71
1.00
Sr
0.74
0.61
-0.05
0.20
0.14
0.74
0.98
1.00
Pain on nominated
activity VAS*
0.27
0.23
0.02
0.19
0.19
0.07
0.29
0.29
Pain on nominated
activity VAS*
Colour
Scale:
1.00
0.75
0.50
0.25
0.00
-0.25
-0.50
-0.75
-1.00
1.00
*Observations are 64 due to 8 patients missing VAS observations (patients did not complete question)
 The parameter with the strongest correlation with change in VAS
IMAGE ANALYSIS: DYNAMIC PARAMETERS
 We used the extended Tofts model
𝑡
𝐾 𝑡𝑟𝑎𝑛𝑠
(𝑡−𝜏)
−
FIGURE 3: DIAGRAM
OF DYNAMIC
PARAMETERS
𝑑𝜏
𝐶𝑡 𝑡 = 𝑣𝑝 𝐶𝑝 𝑡 + 𝐾 𝑡𝑟𝑎𝑛𝑠 0 𝐶𝑝 (𝜏)𝑒 𝑣𝑒
which is a solution of the pharmacokinetic
ve
trans
ve
equation, to calculate the parameters K
Ktrans
(permeability), ve (extra-cellular space) and vp
vi
(plasma space) at every image voxel (Figure 3).
vi
 We calculated parameters at each voxel based
vp
upon the time series of intensity Si (i=0,..,n) over
the dynamic sequence: (a) the maximum gradient Gmax,
(b) the maximum relative enhancement Sr=Smax/S0, and
(c) the late relative enhancement Sl=(Sn+…+Sn-3)/(4*S0)
pain was change in Sl (r=0.29, b=0.64; 95% CI 0.11 to 1.17;
p=0.02), which is a stronger correlation than change in volume V*s
(r=0.19, b=0.18; 95% CI -0.05 to 0.41; p=0.13). Other parameters
with strong correlations to change in VAS pain were change in Sr
(r=0.29, b=0.56; 95% CI 0.09 to 1.03; p=0.02) and change in Ktrans
(r=0.27, b=26.93; 95% CI 2.24 to 51.63; p=0.03).
CONCLUSION
 Dynamic measures of synovial enhancement correlate more
strongly with pain reduction after intraarticular steroid injection than
static measures of change in synovial volume.
 In studies examining synovial response to treatment in osteoarthritis,
dynamic parameters may optimize the detection of treatment effects.
ACKNOWLEDGEMENTS
Thanks to Ross Little and Sue Cheung of Imaging Sciences, University of Manchester, and to Gio
Buccanorsi of Bioxydyn, for their insights into the DCE-MRI modelling used in this work, gained from
their experiences in oncological studies over a number of years.
Supported by Arthritis Research UK programme grant 18676; Manchester Academic Health Science
Centre (MAHSC); Salford Royal NHS Foundation Trust; National Institute for Health Research (NIHR)