Background
Patello-femoral Joint Osteoarthritis (PFJOA) is a common cause of knee pain in middle aged adults. In a recent randomised controlled trial of brace therapy in persons with symptomatic PFJOA we showed that a flexible sleeve knee brace resulted in a significant improvement in pain after 6 weeks and a reduction in bone marrow lesion (BML) volume in the PFJ [
1]. The two structures in the knee that are both innervated by nociceptive fibers and reported to be causally related to knee pain are bone [
2] and synovitis [
3,
4]. In the bone, the most prominently assessed abnormality correlated with pain has been bone marrow lesions [
5]. While hyaline cartilage pathology is the signature feature of osteoarthritis [
6], this cartilage is not innervated, and it is not clear whether it is a source of pain. The change in pain during the trial was not correlated significantly with change in the BML volume, suggesting other mechanisms explain the pain reduction. Synovial tissue volume decrease has been linked with pain in observational studies [
3,
4], but synovial volume assessed in the trial using static contrast enhanced magnetic resonance imaging (CE-MRI) did not shrink with the intervention [
1].
Static measures of synovial volume may be less sensitive to pain than measures of synovial perfusion, assessed using dynamic contrast enhanced Magnetic Resonance Imaging (DCE-MRI) is a technique that utilises repeated imaging sequences of the joint whilst injecting contrast agent systemically [
7]. This allows enhancement rates of tissues to be calculated as they are perfused by contrast agent. The rate of tissue enhancement has been shown to be more closely linked to active joint inflammation in rheumatoid arthritis (RA) than changes to static tissue volume measures alone, and correlates more strongly with change in pain following intra-articular steroid therapy [
8]. We have recently shown that in knee OA, intraarticular steroid treatment leads to a major reduction in perfusion of the synovium as shown by DCE-MRI and that this reduction is far better correlated with pain reduction than measures of static synovial volume [
9]. Since braces may diminish contact stress across the joint, leading to less microscopic damage and perhaps less need for the synovium to clear this debris, we hypothesised that the reduction in pain observed following brace use in our recent trial might be explained by changes in synovitis as assessed using DCE-MRI parameters. We therefore undertook a secondary analysis of the trial findings to examine this question.
Discussion
Our result suggest that synovitis, assessed using a sensitive imaging technique, does not improve following sleeve brace wearing. Change in synovitis does not explain the observed improvement in pain. Within the control group there was a small reduction in RER (p = 0.04) and Ktrans (p = 0.05) variables over the study period suggesting a reduction in synovitis in this group, however, the magnitude of the changes was small and probably not clinically significant.
The DCE technique is a more sensitive method of detecting synovitis than static contrast enhanced imaging. Axelsen et al. demonstrated in 17 RA patients that intra-operative knee synovial biopsies showed histological inflammation which was highly correlated with changes in rates of synovial enhancement on pre-surgical T1 weighted MR images, especially the RER (spearman’s correlation coefficient = 0.70,
p = 0.001) [
8]. A review by Hodgson et al. was consistent with this; the RER was shown in multiple RA studies to correlate with histological, physiological and clinical disease activity changes [
13]. Synovitis assessed using DCE-MRI was more strongly associated with change in pain following steroid injection than static MRI imaging [
14].
As noted earlier, the two structures consistently linked to pain in knee OA have been bone marrow lesions and synovitis (bone attrition has also been linked to pain but would be unlikely to change in 6 weeks and its change is not readily measurable). The absence of any association with change in synovitis assessed using DCE-MRI suggests that the reduction in pain following brace wearing is not due to change in synovitis and that other mechanisms may be operating. What then is the mechanism for pain reduction? We did find in the trial that the patellar brace caused a reduction in BML volume in the patellofemoral compartment but that reduction was not significantly correlated with pain reduction. Although change in BML volume did not explain the pain reduction, it is possible that change in other structural features may have contributed. Ultimately, while pain improved, this was not necessarily accompanied by structural changes (although we may not have had the power to show that the reduction in BML volume was correlated with the pain reduction). The decrease in focal stress across the patellofemoral joint may have decreased nociceptive stimuli without causing a change in imaging parameters, and it is possible that our imaging approaches to pain are still too insensitive to detect the change induced.
This study was a secondary analysis of a trial of 126 patients. The original design did not include a formal sample size calculation for the DCE-MRI analysis. Instead, we made use of all available DCE-MRI scans collected during the course of the trial. Given the observed DCE-MRI trial data, we can calculate an estimated sample size for a future trial of the same design. Using RER as the primary outcome, the observed RER values for the change in the brace (mean change = +0.003; SD = 0.014) and no-brace group (mean change = −0.005; SD = 0.016), alpha of 0.05 and 80% power, a parallel-groups clinical trial testing for differences in the change in RER between the brace and no-brace group after 6 weeks would require 59 patients per group, a similar number to the trial findings presented here. A design using Ktrans as the primary outcome, using observed values for the brace and no-brace group, would require 137 patients per group. Based on these estimates, it is possible but unlikely that our study was null because of inadequate power. We note that we found significant effects of dynamic measures of synovitis but in the opposite direction expected and that pain reduction effects were highly statistically significant.
The reduction in pain seen in the trial was modest but exceeded the minimum clinically important difference reported by Angst et al. (1.3 on a 10 cm scale) [
15].
There are some limitations to be considered. It is possible that the six weeks trial duration may not have been long enough to identify significant physiological changes to synovium in participants who used a brace. This seems unlikely as changes are seen within 2-weeks following an intra-articular steroid injection [
11,
16]. DCE-MRI was taken from a fixed region of interest (ROI) in the knee set on computer software. This is due to the standard Tofts’s equation requirements and the need to select a fixed area of tissue to make each image comparable between subjects. As each participant did not have the same size knee, the ROI varied between participants. This may have led to the fixed ROI window not capturing all the synovitis in each knee. This discrepancy was not recorded; there may be a difference between the groups with the percentage of total synovitis measured. In addition, sampling was done at intervals longer than might be optimal to detect dynamic change. The low temporal resolution of the DCE-MRI sequence (22 s) limits the accuracy of the model, particularly for estimating K
trans. The field of view (FOV) was also limited reflecting the compromise in DCE-MRI between temporal resolution, spatial resolution and FOV in the phase encode directions; these could be improved for measurement of RE
late where high temporal resolution is less important. Also, movement between dynamic images may degrade reproducibility of measurements such as RER. This could be reduced by use of image registration (4).
Acknowledgements
The authors appreciate the assistance of Helen Williams, Laura Heathers, Laura Forsythe and Rosie Perry for their support with the research study.