Abstract
Objectives
Synovitis in symptomatic knee OA (KOA) is common and is associated with joint symptoms. Optimal synovial measurement on MRI is, however, unclear. Our aims were to examine the relationship between MRI measures of synovitis and knee symptoms in symptomatic KOA.
Methods
Data from a randomized, multicentre, placebo-controlled trial (UK-VIDEO) of vitamin-D therapy in symptomatic KOA were utilized. Participants reported knee symptoms using WOMAC at baseline and annually. On contrast-enhanced (CE) MRI, synovial thickness was measured using established, semi-quantitative methods whilst synovial tissue volume (STV) was assessed as absolute STV (aSTV) and relative to the width of femoral condyle (rSTV). STV of the infrapatellar region was also assessed. Associations between synovial measures and symptoms were analysed using multiple linear regression modelling.
Results
No linear association was observed between knee symptoms and synovitis thickness scores. Whole-joint aSTV (0.88, 95% CI: 0.17, 1.59) and infrapatellar aSTV (5.96, 95% CI: 1.22, 10.7) were positively associated with knee pain. Whole-joint rSTV had a stronger association with pain (7.96, 95% CI: 2.60, 13.33) and total scores (5.63, 95% CI: 0.32, 10.94). Even stronger associations were found for infrapatellar rSTV with pain (55.47, 95% CI: 19.99, 90.96), function (38.59, 95% CI: 2.1, 75.07) and total scores (41.64, 95% CI: 6.56, 76.72).
Conclusions
Whole-joint and site-specific infrapatellar STV measures on CE-MRI were associated with knee pain, respectively. Volumes relative to the size of the femoral condyle may be promising outcome measures in KOA trials.
Keywords: synovitis, knee, osteoarthritis, MRI, quantitative, semi-quantitative
Rheumatology key messages
Synovial tissue volume (STV) measures were strongly, and linearly, associated with knee symptoms in symptomatic KOA.
Whole-joint absolute STV and site-specific absolute infrapatellar STV were positively associated with knee pain.
STV measures relative to the size of the femur were strongly associated with knee symptoms.
Introduction
OA of the knee is the most common cause of knee pain among those aged 45 years and older [1] and there is evidence to suggest that prevalence is increasing [2, 3]. Synovial inflammation is present at all stages of knee OA (KOA) and is most likely a secondary phenomenon. Currently, there are no licensed disease-modifying treatments for knee OA with currently available interventions aimed at alleviating painful symptoms and improving function. The current focus is to identify clinically important tissue targets that are related to the underlying pathogenesis of OA.
Synovitis has an important role in KOA [4] with data suggesting that synovitis is an early risk factor for the development of radiographic KOA [5–7] and rapid-onset ‘accelerated KOA’ [8]. Further, data from most observational studies, but not all, suggest that synovitis is associated with structural progression with the evidence suggesting that only those with severe synovitis are at greater risk of progressing in their disease [7, 9, 10]. There is also evidence to suggest that synovitis is associated with pain [11–14], with the degree of synovitis correlating with the degree of knee pain in a dose-response manner [15]. OA is widely accepted to be a heterogeneous disease [16] thus it is likely that the severity of synovitis is likely to fluctuate with symptoms. Synovitis has been shown to resolve in a relatively short time [11] and so has become a prominent treatment target in KOA trials. Currently, there is no consensus over the optimum approach for the assessment of synovitis on MRI in KOA.
There are several markers of synovitis on MRI, which include the volume of joint effusion and increased signal of thickened synovium on fluid sensitive sequences and, the volume of contrast-enhanced (CE) synovial membrane [17–20]. In large epidemiological imaging studies, non-CE MRI is frequently used [10, 21, 22] though this technique does not allow for optimum differentiation of effusion from synovium [23]. Subsequently, CE-MRI is the preferred method of assessment; with data from histological studies supporting strong correlations between CE-MRI and macroscopic evaluation [23]. Furthermore, signal changes in Hoffa’s fat pad (infrapatellar region) have been used as surrogate markers of synovial activation [24]; a sensitive yet non-specific maker of synovitis when using CE-MRI as the reference standard [25]. Synovitis in KOA is frequently assessed using semi-quantitative methods [22, 26, 27], in which scores are used to grade severity of synovitis distension, and quantitatively in which the volume of the synovial tissue is directly measured [28].
Imaging biomarkers used to evaluate synovitis are likely to play an increasing role in identifying participants for OA clinical trials and assessing treatment efficacy in which synovitis is the treatment target. Our aim was to explore the relationship between different measures of synovitis and symptoms in symptomatic KOA using CE-MRI.
Methods
Data source and sample size
We used cross-sectional data from the Vitamin D in OA (UK VIDEO) trial [29] (ISRCTN94818153). VIDEO was a 3-year double-blind, randomized, placebo-controlled trial involving five UK NHS centres, which examined the effect of vitamin D therapy on radiographic joint space narrowing and symptoms in men and women with symptomatic KOA [29]. Details of the original VIDEO study have been published previously [29]. In brief, eligible participants had radiological evidence of KOA at the medial tibio-femoral knee compartment [Modified Kellgren & Lawrence (K&L) [30] score of 2–3], joint space width >1 mm and had knee pain for most days of the previous month. A total of 474 participants were randomized, within centres, to receive either oral vitamin D (800 IU/daily) or matching placebo in a 1:1 ratio.
A subsample of participants recruited at Southampton (n = 174) had MRIs performed. Participants eligible for this study had sagittal and/or axial T1-weighted (T1-w) fat suppressed (FS) CE MRIs, an axial proton-density-weighted (PD-w) FS and/or coronal short tau inversion recovery (STIR) scan for the corresponding visit, synovitis thickness scores, synovial tissue volume (STV) measures and WOMAC symptom data at, at least, a single visit across follow-up. Each participant contributed a single visit to the analysis. Ethical approval was not required for any aspect of the work presented in this manuscript.
Magnetic resonance imaging
Images were acquired on a 1.5 T MRI scanner (Signa (GE Healthcare)) using a dedicated phased-array knee coil [14]. Sagittal and axial post-contrast T1-w fat suppressed (FS) (repetition time (TR) = 600–800 ms, echo time (TE) = 12.5–16.2 ms, acquisition matrix 256 × 160, slice gap = 0.6 mm, slice thickness = 3 mm), axial proton density weighted (PD-w) FS (TR = 3800–4820 ms, TE = 31.2–32.5 ms, matrix 256 × 192, slice gap = 0.2 mm, slice thickness = 4 mm) and coronal short tau inversion recovery (STIR) (TR = 3000–4760 ms, TE = 46.1–56.9 ms, matrix 256 × 192, slice gap = 0.3 mm, slice thickness = 3 mm) sequences were acquired. For image acquisition, participants were positioned supine for scanning. An intravenous injection of gadodiamide [0.2 ml/kg body weight (Omniscan, GE Healthcare)] was administered 3 minutes prior to the acquisition of the first CE scan [14]; with all scans acquired within 11 minutes of contrast administration.
Quantitative assessment of synovial tissue volume
A single reader (T.A.P) performed segmentation of STV (mm3) using a semi-automated approach that has been described previously [31]. In brief, the software segments enhancing STV (on CE-MRI) based on a threshold, as selected by the user, within a 3 D-mask that is applied to the target image [31]. STV measured across the whole joint was termed total absolute STV (aSTV). Segmentation of STV was performed using sagittal T1-w fat suppressed CE scans on the index (most painful) knee. Reliability of STV assessment has been assessed previously and was found to be excellent for both intra- (ICC3,1=0.99) and inter-observer agreement (ICC3,1=0.83) [13].
Relative measures of STV and infrapatellar synovitis volume
The total STV in the joint compartment relative to femoral condyle width was calculated and was expressed as a single outcome; total relative STV (rSTV). To calculate relative volume, we assessed the width of the femoral condyle on a total of four consecutive slices (where the femoral condyle was at its most visible and at its greatest dimension) for each participant. All images were maximized within the software window in order to standardise measurements. Width measurements were manually recorded, on a Dell monitor (1920 × 1080 pixel resolution, 23-inch), for each participant in accordance with criteria defined by Hunter et al. [27]; for the anatomical delineation of the femur into trochlea and weight-bearing regions (see Fig. 1). Width measurements were averaged with total relative values calculated as follows; [total absolute STV (mm3)/mean femoral width (mm)].
Fig. 1.
Sagittal T1-w fat suppressed (FS) contrast-enhanced MRI of a symptomatic osteoarthritic knee
(A) Delineation of the femur for femoral condyle width measurement and (B) region of interest defined for the infrapatellar (Hoffa’s) fat pad.
We further segmented high signals on CE-MRI in the infrapatellar region (Fig. 1) and termed this volume total absolute infrapatellar STV; referred throughout as infrapatellar aSTV. The infrapatellar region was defined as the region directly adjacent to the inferior patella pole [27]. We further included high signals directly adjacent to the lateral menisci as there is evidence to suggest that localized meniscal damage is associated with surrounding synovitis [32]. Total relative infrapatellar STV, referred to as infrapatellar rSTV, was calculated as [total absolute infrapatellar STV (mm3)/mean femoral width (mm)].
Semi-quantitative assessment of synovial thickness
Synovial thickness was examined in a subsample (n = 107) of VIDEO as part of a previous study [14]. Synovial thickness was assessed using a semi-quantitative grading system which has been previously validated [33]. In brief, a single musculoskeletal radiologist with over 8 years’ experience in image assessment in knee OA scored the MRIs for synovial thickness [14]. An ordinal score of 0–3 [0 = normal, 1 = mild (<2 mm), 2 = moderate (2–4 mm) and 3 = severe (>4 mm)] was assigned across 11 regions including the infrapatellar region. Thickness was assessed on either sagittal or axial post-contrast sequences [14]. We created a composite measure of total synovial thickness that was equal to the sum of all synovitis scores. We then categorized total synovial thickness as normal (0–4), mild (5–8), moderate (9–12) and severe (≥13) in accordance with previous methods [33].
Assessment of symptoms
Pain, function and stiffness symptoms were assessed using the Western Ontario and McMaster Universities (WOMAC) questionnaire. Each item of WOMAC was scored on a visual analogue scale (VAS) from 0–100 mm (0 = no pain/disability). WOMAC total was generated as a composite of pain, function and stiffness. Scores corresponded to symptoms experienced within the last 48 hrs.
Statistical methods
Characteristics of the study participants are presented as means and standard deviations for normally distributed variables and medians and inter-quartile range (IQR) for non-normally distributed variables. Data were analysed using STATA (version 15.1, StataCorp., College Station, TX, USA). To examine the relationship between synovitis (continuous or categoric measures) and symptoms, we used multiple linear regression with: (i) total aSTV; (ii) total rSTV; (iii) infrapatellar aSTV; (iv) infrapatellar rSTV; (v) whole joint synovitis thickness score; and (vi) infrapatellar synovitis thickness score as the respective exposures and WOMAC symptoms (pain, function, stiffness and total) as the outcomes. Synovitis score was included as a categoric exposure as it was assumed that the relationship between semi-quantitatively assessed synovitis and knee symptoms would be non-linear. We formally tested the assumptions of linear regression and confirmed that there were no violations. All regression models were adjusted for potential confounders which included age, sex, body mass index (BMI) and the presence/absence of Heberden’s nodes. We did not adjust for the allocation of treatment intervention as it has been previously reported that vitamin D therapy has no observed effect on the outcomes described here [34].
Results
Subjects
In total, 96 participants had CE-MRI scans, symptom data, synovitis thickness scores, total aSTV and total rSTV and infrapatellar STV measured at least a single visit across follow-up. Participants’ mean age (s.d.) was 65.4 (± 8.1) years and most participants were female. Table 1 shows the characteristics of the included participants.
Table 1.
Clinical and imaging characteristics of the study participants (n = 96)
| Variable | |
|---|---|
| Females, n (%) | 63 (65.6) |
| Index knee, n (% Right) | 53 (55.2) |
| Body mass index (BMI) (kg/m2) | 28.8 (4.6) |
| Baseline Kellgren–Lawrence grade (medial/lateral) in index knee | |
| Grade 1, n (%) | 19 (19.8) |
| Grade 2, n (%) | 40 (41.6) |
| Grade 3, n (%) | 33 (34.4) |
| Grade 4, n (%) | 4 (4.2) |
| WOMACa | |
| Pain score | 33.8 (21.0) |
| Stiffness score | 45.8 (25.3) |
| Function score | 37.0 (22.1) |
| Total score | 37.0 (21.1) |
| Presence of Heberden’s nodes, (yes: n, %) | 69 (71.9) |
| Total absolute STV (mm3) | 9900.6 (6537.7) |
| Relative total STV | 131.8 (86.9) |
| Total absolute infrapatellar STV (mm3) | 2012.0 (1042.8) |
| Total relative infrapatellar STV | 26.8 (14.0) |
Results are shown as means (s.d.) or frequencies (%). aWOMAC: Western Ontario and McMaster Universities Osteoarthritis Index: visual analogue scale (VAS) used to score pain, function, stiffness and total respectively from 0 to 100 units (0 = no pain / disability, 100 = high pain / disability). STV, synovial tissue volume.
Two participants were excluded from all analysis as they showed evidence of high normalized residual squared values and a high degree of leverage over the regression models (data not shown); exclusion is in line with current recommendations [35]. We assessed a single visit per participant with synovitis measured at the baseline visit in 45 (47.9%) participants, while 22 (23.4%), 23 (24.5%) and 4 (4.2%) participants had 12, 24- and 36-month follow-up visits assessed respectively. WOMAC scores were captured at the time of MRI acquisition in all participants. In those with missing scores (n = 2), data at the following visit (6-months post-MRI) was used. All participants had evidence of synovitis on CE-MRI. In addition, whilst inclusion to the primary VIDEO trial specified that all participants must have a KL grade of 2–3, upon re-evaluation of the radiographs some participants were re-graded as KL1s and KL4s.
Total absolute STV and infrapatellar STV and symptoms
In multivariate analysis, there was a statistically significant association between total aSTV and pain (0.88, 95% CI: 0.17, 1.59), though not with function (0.46, 95% CI: −0.28, 1.19), stiffness (0.53, 95% CI: −0.37, 1.42) and total score (0.55, 95% CI: −0.15, 1.26); see Table 2. Similarly, there was a statistically significant association between infrapatellar aSTV and pain (5.96, 95% CI: 1.22, 10.7); with an increase in volume associated with worsening knee pain (Table 2). There was, however, no statistically significant association between infrapatellar aSTV and function (3.31, 95% CI: −1.54, 8.17), stiffness (2.5, 95% CI: −3.46, 8.46) and total (3.8, 95% CI: −0.88, 8.48).
Table 2.
Association between synovitis volume and symptoms
| Outcome | Univariate (n = 94) | Multivariate a (n = 94) | Multivariateb (n = 94) | Multivariatec (n = 94) |
|---|---|---|---|---|
| Total absolute STVd | ||||
| WOMACe pain | 0.89 (0.17, 1.61), 0.02 | 0.89 (0.17, 1.62), 0.02 | 0.93 (0.22, 1.64), 0.01 | 0.88 (0.17, 1.59), 0.02 |
| Stiffness | 0.48 (−0.42, 1.38), 0.29 | 0.49 (−0.4, 1.38), 0.28 | 0.53 (−0.36, 1.41), 0.24 | 0.53 (−0.37, 1.42), 0.24 |
| Function | 0.41 (−0.37, 1.19), 0.3 | 0.41 (−0.37, 1.19), 0.3 | 0.49 (−0.24, 1.21), 0.19 | 0.46 (−0.28, 1.19), 0.22 |
| Total | 0.52 (−0.23, 1.26), 0.17 | 0.52 (−0.22, 1.26), 0.17 | 0.58 (−0.11, 1.28), 0.1 | 0.55 (−0.15, 1.26), 0.12 |
| Total absolute infrapatellar STVd | ||||
| Pain | 5.4 (0.63, 10.16), 0.03 | 5.86 (1.07, 10.65), 0.02 | 6.31 (1.6, 11.03), 0.01 | 5.96 (1.22, 10.7), 0.01 |
| Stiffness | 1.41 (−4.51, 7.34), 0.64 | 2.15 (−3.76, 8.06), 0.47 | 2.5 (−3.38, 8.38), 0.4 | 2.5 (−3.46, 8.46), 0.41 |
| Function | 2.09 (−3.04, 7.22), 0.42 | 2.63 (−2.52, 7.78), 0.31 | 3.5 (−1.3, 8.31), 0.15 | 3.31 (−1.54, 8.17), 0.18 |
| Total | 2.73 (−2.16, 7.62), 0.27 | 3.27 (−1.63, 8.16), 0.19 | 4.01 (−0.62, 8.64), 0.09 | 3.8 (−0.88, 8.48), 0.11 |
All results presented with 95% CIs and P-values. Statistically significant results (P ≥0.05) are shown in bold. aAdjusted for sex. bAdjusted for sex, age, body mass index (BMI). cAdjusted for sex, age, body mass index (BMI) and presence of Heberden’s nodes. dAbsolute effects sizes from the linear regression models reflect the change in WOMAC score for a 1 cm3 increase in volume. eWOMAC = Western Ontario and McMaster Universities Osteoarthritis Index: visual analogue scale (VAS) used to score knee symptoms from 0–100 (0 = no pain/disability to 100 = high pain/disability). STV, synovial tissue volume.
Total relative STV and infrapatellar STV and symptoms
In multivariate analysis, there was a statistically significant association between total rSTV and knee pain (7.96, 95% CI: 2.60, 13.33) and total score (5.63, 95% CI: 0.32, 10.94) though there was no association with function (4.96, 95% CI: −0.56, 10.49) and stiffness (5.47, 95% CI: −1.29, 12.22), respectively; see Table 3. Infrapatellar rSTV was statistically significantly associated with pain (55.47, 95% CI: 19.99, 90.96), function (38.59, 95% CI: 2.1, 75.07) and total score (41.64, 95% CI: 6.56, 76.72) though not with stiffness (32.61, 95% CI: −12.45, 77.67). The reported coefficients for these infrapatellar rSTVs appear large (e.g. the coefficient of 55.47 implies that for a 1 unit increase in infrapatellar rSTV, this reflects a corresponding change in WOMAC pain score of 55.47 points), though this accurately reflects volumes that are typically small.
Table 3.
Association between relative synovitis volume and symptoms
| Outcome | Univariate (n = 94) | Multivariatea (n = 94) | Multivariateb (n = 94) | Multivariatec (n = 94) |
|---|---|---|---|---|
| Total relative STVd | ||||
| WOMACe pain | 8.15 (2.7, 13.6), 0.004 | 8.02 (2.56, 13.48), 0.004 | 8.29 (2.93, 13.64), 0.003 | 7.96 (2.60, 13.33), 0.004 |
| Stiffness | 5.47 (−1.34, 12.29), 0.11 | 5.19 (−1.58, 11.95), 0.13 | 5.45 (−1.24, 12.13), 0.11 | 5.47 (−1.29, 12.22), 0.11 |
| Function | 4.84 (−1.08, 10.75), 0.11 | 4.64 (−1.27, 10.54), 0.12 | 5.13 (−0.35, 10.61), 0.07 | 4.96 (−0.56, 10.49), 0.08 |
| Total | 5.58 (−0.03, 11.19), 0.051 | 5.39 (−0.21, 10.99), 0.06 | 5.82 (0.55, 11.09), 0.03 | 5.63 (0.32, 10.94), 0.04 |
| Total relative infrapatellar STVd | ||||
| Pain | 52.92 (16.78, 89.06), 0.005 | 54.26 (18.17, 90.35), 0.004 | 57.33 (21.84, 92.81), 0.002 | 55.47 (19.99, 90.96), 0.003 |
| Stiffness | 27.9 (−17.5, 73.3), 0.23 | 30.29 (−14.65, 75.23), 0.18 | 32.59 (−12.07, 77.24), 0.15 | 32.61 (−12.45, 77.67), 0.15 |
| Function | 31.75 (−7.43, 70.93), 0.11 | 33.46 (−5.54, 72.46), 0.09 | 39.53 (3.29, 75.76), 0.03 | 38.59 (2.1, 75.07), 0.04 |
| Total | 35.87 (−1.33, 73.08), 0.06 | 37.56 (0.59, 74.56), 0.047 | 42.69 (7.82, 77.56), 0.02 | 41.64 (6.56, 76.72), 0.02 |
All results presented with 95% CIs and P-values. Statistically significant results (P ≥0.05) are shown in bold. aAdjusted for sex. bAdjusted for sex, age, body mass index (BMI). cAdjusted for sex, age, body mass index (BMI) and presence of Heberden’s nodes. dAbsolute effects sizes from the linear regression models reflect the change in WOMAC score for a 1 cm3 increase in relative volume. eWOMAC = Western Ontario and McMaster Universities Osteoarthritis Index: visual analogue scale (VAS) used to score knee symptoms from 0–100 (0 = no pain/disability to 100 = high pain/disability). STV, synovial tissue volume.
Total synovitis thickness scores and symptoms
In multivariate analysis, there was no statistically significant association between severity of whole joint synovitis thickness scores and symptoms (see Table 4). In participants with mild synovial thickness, there was no statistically significant association with pain (4.71, 95% CI: −12.29, 21.7), stiffness (−1.55, 95% CI: −22.48, 19.38), function (5.64, 95% CI: −11.59, 22.86) and total score (4.86, 95% CI: −11.77, 21.5). Further, there was no statistically significant association between moderate synovial thickness and pain (0.46, 95% CI: −16.14, 17.06), stiffness (4.86, 95 CI%: −15.58, 25.3), function (6.73, 95% CI: −10.09, 23.54) and total score (5.29, 95% CI: −10.96, 21.53). Lastly, there was no statistically significant association between severe synovial thickness and pain (9.22, 95% CI: −5.97, 24.41), stiffness (7.04, 95% CI: −11.67, 25.75), function (8.04, 95% CI: −7.35, 23.43) and total score (8.22, 95% CI: −6.65, 23.09).
Table 4.
Association between total synovitis thickness severity and symptoms
| Outcome | Univariate (n = 94) | Multivariatea (n = 94) | Multivariateb (n = 94) | Multivariatec (n = 94) |
|---|---|---|---|---|
| Total synovitis thickness scored | ||||
| WOMAC e pain | ||||
| Mild (n=16) | 3.86 (−13.45, 21.17), 0.66 | 3.58 (−13.77, 20.93), 0.68 | 3.87 (−13.28, 21.02), 0.66 | 4.71 (−12.29, 21.7), 0.58 |
| Moderate (n=20) | 0.07 (−16.61, 16.75), 0.99 | −0.11 (−16.81, 16.6), 0.99 | 0.09 (−16.68, 16.86), 0.99 | 0.46 (−16.14, 17.06), 0.96 |
| Severe (n=49) | 7.16 (−7.91, 22.23), 0.35 | 6.53 (−8.63, 21.69), 0.39 | 7.8 (−7.46, 23.07), 0.31 | 9.22 (−5.97, 24.41), 0.23 |
| Stiffness | ||||
| Mild | −1.89 (−22.96, 19.17), 0.86 | −2.51 (−23.41, 18.39), 0.81 | −1.68 (−22.46, 19.1), 0.87 | −1.55 (−22.48, 19.38), 0.88 |
| Moderate | 4.1 (−16.19, 24.39), 0.69 | 3.7 (−16.42, 23.83), 0.72 | 4.81 (−15.51, 25.12), 0.64 | 4.86 (−15.58, 25.3), 0.64 |
| Severe | 6.05 (−12.29, 24.38), 0.51 | 4.64 (−13.62, 22.9), 0.62 | 6.82 (−11.67, 25.32), 0.47 | 7.04 (−11.67, 25.75), 0.46 |
| Function | ||||
| Mild | 6.03 (−12.3, 24.35), 0.52 | 5.59 (−12.68, 23.87), 0.55 | 5.2 (−11.97, 22.37), 0.55 | 5.64 (−11.59, 22.86), 0.52 |
| Moderate | 7.96 (−9.69, 25.62), 0.37 | 7.69 (−9.91, 25.28), 0.39 | 6.53 (−10.26, 23.32), 0.44 | 6.73 (−10.09, 23.54), 0.43 |
| Severe | 7.55 (−8.4, 23.5), 0.35 | 6.56 (−9.41, 22.52), 0.42 | 7.3 (−7.99, 22.58), 0.35 | 8.04 (−7.35, 23.43), 0.3 |
| Total | ||||
| Mild | 4.93 (−12.57, 22.44), 0.58 | 4.52 (−12.93, 21.97), 0.61 | 4.37 (−12.25, 20.98), 0.6 | 4.86 (−11.77, 21.5), 0.56 |
| Moderate | 6.02 (−10.84, 22.88), 0.48 | 5.75 (−11.05, 22.56), 0.5 | 5.07 (−11.18, 21.31), 0.54 | 5.29 (−10.96, 21.53), 0.52 |
| Severe | 7.36 (−7.87, 22.59), 0.34 | 6.41 (−8.84, 21.66), 0.41 | 7.38 (−7.41, 22.16), 0.32 | 8.22 (−6.65, 23.09), 0.28 |
All results were in comparison to normal (0 = score) levels of synovial thickness (n = 9). All results presented with 95% CIs and P-values. aAdjusted for sex. bAdjusted for sex, age, body mass index (BMI). cAdjusted for sex, age, body mass index (BMI) and presence of Heberden’s nodes. dAbsolute effects sizes from the linear regression models refer to the increase in WOMAC score for a 1 unit increase in severity score. eWOMAC = Western Ontario and McMaster Universities Osteoarthritis Index: visual analogue scale (VAS) used to score knee symptoms from 0–100 (0 = no pain/disability to 100 = high pain/disability).
Infrapatellar synovitis thickness scores and symptoms
In a fully adjusted model, there was no statistically significant association between mild infrapatellar synovitis thickness and pain (2.56, 95% CI: −7.8, 12.91), stiffness (−1.39, 95% CI: −14.12, 11.34), function (3.37, 95 CI: −6.95, 13.7) and total score (2.81, 95% CI: −7.21, 12.83); see Table 5. Further, there was no statistically significant association between moderate infrapatellar synovitis thickness and pain (−4.00, 95% CI: −14.96, 6.97), stiffness (−0.43, 95% CI: −13.91, 13.05), function (−5.55, 95% CI: −16.49, 5.39) and total score (−4.8, 95% CI: −15.41, 5.82). Lastly, there was no statistically significant association between severe infrapatellar synovitis thickness and pain (10.09, 95% CI: −15.89, 36.07), stiffness (10.58, 95% CI: −21.35, 42.52), function (−0.76, 95% CI: −26.67, 25.15) and total score (2.45, 95% CI: −22.69, 27.59).
Table 5.
Association between infrapatellar synovitis thickness severity and symptoms
| Outcome | Univariate (n = 94) | Multivariatea (n = 94) | Multivariateb (n = 94) | Multivariatec (n = 94) |
|---|---|---|---|---|
| Total infrapatellar synovitis thickness scored | ||||
| WOMAC e pain | ||||
| Mild (n=33) | 2.79 (−7.32, 12.89), 0.59 | 2.31 (−7.84, 12.45), 0.65 | 1.63 (−8.73, 12.0), 0.76 | 2.56 (−7.8, 12.91), 0.63 |
| Moderate (n=23) | −3.57 (−14.75, 7.61), 0.53 | −3.69 (−14.86, 7.49), 0.51 | −3.88 (−14.93, 7.17), 0.49 | −4.00 (−14.96, 6.97), 0.47 |
| Severe (n=3) | 7.84 (−17.22, 32.9), 0.54 | 9.28 (−15.92, 34.47), 0.47 | 10.76 (−15.41, 36.92), 0.42 | 10.09 (−15.89, 36.07), 0.44 |
| Stiffness | ||||
| Mild | 0.1 (−12.25, 12.45), 0.99 | −0.87 (−13.13, 11.39), 0.89 | −1.42 (−13.99, 11.15), 0.82 | −1.39 (−14.12, 11.34), 0.83 |
| Moderate | −0.04 (−13.7, 13.63), 0.99 | −0.27 (−13.78, 13.24), 0.97 | −0.42 (−13.82, 12.98), 0.95 | −0.43 (−13.91, 13.05), 0.95 |
| Severe | 5.38 (−25.24, 36.01), 0.73 | 8.28 (−22.18, 38.73), 0.59 | 10.6 (−21.13, 42.33), 0.51 | 10.58 (−21.35, 42.52), 0.51 |
| Function | ||||
| Mild | 6.06 (−4.47, 16.6), 0.26 | 5.47 (−5.08, 16.02), 0.31 | 2.79 (−7.46, 13.05), 0.59 | 3.37 (−6.95, 13.7), 0.52 |
| Moderate | −4.52 (−16.18, 7.14), 0.44 | −4.66 (−16.29, 6.96), 0.43 | −5.48 (−16.41, 5.45), 0.32 | −5.55 (−16.49, 5.39), 0.32 |
| Severe | 0.25 (−25.88, 26.38), 0.99 | 2.02 ( −24.18, 28.22), 0.88 | −0.34 ( −26.22, 25.54), 0.98 | −0.76 (−26.67, 25.15), 0.95 |
| Total | ||||
| Mild | 4.89 (−5.22, 15.0), 0.34 | 4.29 (−5.82, 14.4), 0.4 | 2.21 (−7.75, 12.16), 0.66 | 2.81 (−7.21, 12.83), 0.58 |
| Moderate | −3.94 (−15.13, 7.24), 0.49 | −4.09 (−15.23, 7.05), 0.47 | −4.72 (−15.34, 5.89), 0.38 | −4.8 (−15.41, 5.82), 0.37 |
| Severe | 2.27 (−22.79, 27.32), 0.86 | 4.06 (−21.05, 29.17), 0.75 | 2.89 (−22.25, 28.02), 0.82 | 2.45 (−22.69, 27.59), 0.85 |
All results were in comparison to normal (0 = score) levels of synovial thickness (N = 35). All results presented with 95% CIs and P-values. aAdjusted for sex. bAdjusted for sex, age, body mass index (BMI). cAdjusted for sex, age, body mass index (BMI) and presence of Heberden’s nodes. dAbsolute effects sizes from the linear regression models refer to the increase in WOMAC score for a 1 unit increase in severity score. eWOMAC = Western Ontario and McMaster Universities Osteoarthritis Index: visual analogue scale (VAS) used to score knee symptoms from 0–100 (0 = no pain/disability to 100 = high pain/disability).
Discussion
In this study, using CE-MRI data from a randomized trial of symptomatic KOA, both absolute and relative measures of whole joint STV and site-specific infrapatellar STV were associated with knee symptoms. There was no observed association between synovial thickness scores and knee symptoms.
Several studies have shown an association between semi-quantitative and quantitative MRI measures of synovitis and symptoms in symptomatic KOA though the strength of the relationship has been shown to vary. O’Neill and colleagues reported in a trial of intra-articular corticosteroid injection therapy in symptomatic KOA that synovitis volume was positively associated with increasing knee pain (−1.13, 95% CI: −1.87, −0.39); with a reduction in score indicating an increase in pain [11]. Similarly, in two separate studies using different samples of the UK VIDEO study, synovial thickness scores (1.82, 95% CI: 0.05, 3.58) [14] and whole joint STV (b = 2.2, 95% CI: 0.6, 3.7) [13] were associated with knee pain; with an increase in severity associated with worsening pain. We go beyond these studies to describe the association between different measures of synovitis and symptoms using CE-MRI in the same study sample, thereby allowing for within-study comparisons.
We observed a linear association between STV (absolute and relative measures) and knee pain; however, we did not observe an association between synovitis thickness (whole joint and infrapatellar) scores and symptoms. A possible explanation for this could be due to differences in the structure assessed across CE-MRI sequences. Semi-quantitative scores assess synovial thickness which, whilst a surrogate of synovitis [23, 36], may be inclusive of non-active inflammation with active inflammation. In contrast, quantitative assessment of volume captures active synovial inflammation, as distinct from effusion, represented by signal enhancement at the synovial membrane. Our study may also have been insufficiently powered across levels of synovial thickening to detect true associations. The observed associations between both absolute and relative measures of STV and multiple WOMAC subunits would, however, give confidence that our study was suitably powered.
To our knowledge, this is the first study to have examined the cross-sectional relationship between relative measures of STV and symptoms using CE-MRI in symptomatic KOA. There is some evidence to suggest that the size of the supra-patellar pouch is associated with knee size [37]; thus, we hypothesized that those with a greater bone size may have increased STV independent of disease severity. We observed that whole-joint STV and infrapatellar STV relative to the size of the femoral condyle were more strongly associated with knee pain compared with absolute measures. The method presented here for calculating relative STV and site-specific relative infrapatellar STV could be readily applied to similar studies of symptomatic knee OA. Future work includes applying this method of calculating relative STV measures to other knee OA cohorts and clinical trial datasets; to confirm the suitability and measurement error of this approach.
Evidence from observational studies have shown a relationship between Hoffa’s synovitis and risk of radiographic KOA [5, 6, 38, 39]. There is, however, little data concerning the relationship between Hoffa’s synovitis and pain despite evidence supporting the frequent involvement of the infrapatellar region [24]. Hill et al. showed that change in infrapatellar synovitis was associated with change in knee pain (4.89, 95% CI: 0.42, 9.36) [10]. Similarly, we observed a relationship between pain and infrapatellar aSTV (5.96, 95% CI: 1.22, 10.7) and we also observed a relationship between infrapatellar rSTV and pain (55.47, 95% CI: 19.99, 90.96). The magnitude of the effect was, however, greatest when using relative measures, suggesting that there needs to be consideration of the heterogeneity in knee joint size in studies of KOA and synovitis.
The main strength to this study was that the assessment of synovitis was performed on CE-MRI. Although we were unable to compare histological findings against MRI measures of synovitis, there is strong evidence to support the correlations between CE-MRI assessed synovitis and histology [23].
There are several potential limitations to our study. Firstly, this was a secondary analysis of a randomized trial and so the study sample reported here was relatively small (n = 94), thereby reducing statistical power and, therefore, our ability to detect true associations. We did, however, observe consistent statistically significant associations between STV and several components of WOMAC across multivariate models, giving confidence to our findings. Further, we measured the femoral condyle width across a total of four slices. While, ideally, femoral condyle width would be measured across all available slices, this was not pragmatic and our methods are in agreement with previous methods used to quantify relative values [40, 41]. Further, we measured femoral condyle width from two points of the subchondral bone, which is in keeping with previous methods [27]. The subchondral bone is, however, subject to OA-related structural changes including erosion and osteophyte development, which may have subsequently affected width measurements; calculating average width measures would, however, reduce the influence of such structures (if present) on the final calculated relative values. A further limitation is the generalisability of our infrapatellar STV measure. There is great variability in the definition of Hoffa’s synovitis [26, 27, 33]. We used a modified version of BLOKS [27] to define infrapatellar STV, which included synovitis directly adjacent to the fat pad and within the infrapatellar region and the intercondylar region extending posteriorly to the lateral menisci. Subsequently, we were unable to differentiate origins of inflammation; that is, inflammation having occurred in response to infrapatellar activation or injury at the menisci. Cartilage volume, meniscal extrusion/injury and bone marrow lesion (BML) volume were not captured as part of the original protocol and so were not adjusted for in our analysis. Subsequently, while we observed a strong, statistically significant relationship between measures of synovitis and knee symptoms, we cannot completely exclude the contribution of the other structural features to knee symptoms. Further work is required to confirm these findings. Lastly, due to the cross-sectional design of the study, we were unable to determine causality. While cross-sectional, the precision of our estimates were, however, likely improved with the addition of data across multiple study visits.
In conclusion, we observed an association between absolute measures of whole-joint STV and site-specific infrapatellar STV and knee symptoms respectively in symptomatic knee OA. Relative measures were more strongly associated with knee symptoms and there was no linear association between synovial thickness and knee symptoms. Relative measures of STV may prove useful outcomes in trials of knee OA.
Acknowledgements
We would like to thank the support of the staff involved in the VIDEO study including the study participants. Further, we would like to express our thanks to Professor Timothy Cootes and Dr Andrew Gait (University of Manchester) for providing access to the synovitis semi-automated segmentation software used for synovial tissue volume quantification. In addition, we would like to thank Professor Frank Roemer for the semi-quantitative scoring of synovial thickness. T.A.P., N.K.A. and S.K. were involved in the conception and design of the study. T.A.P. processed the data, completed the statistical analysis and drafted the manuscript. T.A.P., J.vS. and N.K.A. contributed to the acquisition of data. All authors contributed to the interpretation of data, revising the manuscript and the final approval of the manuscript. All data generated and analysed in this study are available upon reasonable request. Access to data generated in this report should be sent to the corresponding author at thomas.perry@ndorms.ox.ac.uk. Patient Public Involvement (PPI) was not required nor involved with any aspect of the work presented.
Funding: This work was funded by the Versus Arthritis Centre for Sport, Exercise and Osteoarthritis. The funders were not involved in the study design and data collection and interpretation.
Disclosure statement: N.K.A. has received honorariums from Novartis, Alliance for Better Health and Lilly; held advisory board positions (which involved receipt of fees) at Merck, Merck Sharp and Dohme, Roche, Novartis, Smith and Nephew, Q-MED, Nicox, Servier, GlaxoSmithKline, Schering-Plough, Pfizer, and Rottapharm; and received consortium research grants from Alliance for Better Bone Health, Amgen, Novartis, Merck Sharp and Dohme, Servier, Eli Lilly, and GlaxoSmithKline; he has no other relationships or activities that could appear to have influenced the submitted work. The other authors have declared no conflicts of interest.
Data availability statement
All data generated and analysed in this study are available upon reasonable request. Access to data generated in this report should be sent to the corresponding author at thomas.perry@ndorms.ox.ac.uk.
References
- 1. Cross M, Smith E, Hoy D. et al. The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis 2014;73:1323–30. [DOI] [PubMed] [Google Scholar]
- 2. Nguyen U-S, Zhang Y, Zhu Y. et al. Increasing prevalence of knee pain and symptomatic knee osteoarthritis: survey and cohort data. Ann Intern Med 2011;155:725–32. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Lawrence RC, Felson DT, Helmick CG. et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part II. Arthritis Rheum 2008;58:26–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Wang X, Hunter DJ, Jin X, Ding C.. The importance of synovial inflammation in osteoarthritis: current evidence from imaging assessments and clinical trials. Osteoarthritis Cartilage 2018;26:165–74. [DOI] [PubMed] [Google Scholar]
- 5. Felson DT, Niu J, Neogi T. et al. Synovitis and the risk of knee osteoarthritis: the MOST Study. Osteoarthritis Cartilage 2016;24:458–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Atukorala I, Kwoh CK, Guermazi A. et al. Synovitis in knee osteoarthritis: a precursor of disease? Ann Rheum Dis 2016;75:390–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Roemer FW, Guermazi A, Felson DT. et al. Presence of MRI-detected joint effusion and synovitis increases the risk of cartilage loss in knees without osteoarthritis at 30-month follow-up: the MOST study. Ann Rheum Dis 2011;70:1804–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Davis JE, Ward RJ, MacKay JW. et al. Effusion-synovitis and infrapatellar fat pad signal intensity alteration differentiate accelerated knee osteoarthritis. Rheumatology 2019;58:418–26. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Ayral X, Pickering EH, Woodworth TG, Mackillop N, Dougados M.. Synovitis: a potential predictive factor of structural progression of medial tibiofemoral knee osteoarthritis – results of a 1 year longitudinal arthroscopic study in 422 patients. Osteoarthritis Cartilage 2005;13:361–7. [DOI] [PubMed] [Google Scholar]
- 10. Hill CL, Hunter DJ, Niu J. et al. Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis. Ann Rheum Dis 2007;66:1599–603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. O'Neill TW, Parkes MJ, Maricar N. et al. Synovial tissue volume: a treatment target in knee osteoarthritis (OA). Ann Rheum Dis 2016;75:84–90. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Hill CL, Gale DG, Chaisson CE. et al. Knee effusions, popliteal cysts, and synovial thickening: association with knee pain in osteoarthritis. J Rheumatol 2001;28:1330–7. [PubMed] [Google Scholar]
- 13. Perry TA, Parkes MJ, Hodgson RJ, Felson DT, Arden NK, O'Neill TW.. Association between Bone marrow lesions & synovitis and symptoms in symptomatic knee osteoarthritis. Osteoarthritis Cartilage 2020;28:316–23. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. Wallace G, Cro S, Dore C. et al. Associations between clinical evidence of inflammation and synovitis in symptomatic knee osteoarthritis: a cross-sectional substudy. Arthritis Care Res 2017;69:1340–8. [DOI] [PubMed] [Google Scholar]
- 15. Baker K, Grainger A, Niu J. et al. Relation of synovitis to knee pain using contrast-enhanced MRIs. Ann Rheum Dis 2010;69:1779–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Kraus VB, Blanco FJ, Englund M, Karsdal MA, Lohmander LS.. Call for standardized definitions of osteoarthritis and risk stratification for clinical trials and clinical use. Osteoarthritis Cartilage 2015;23:1233–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Ostergaard M. Different approaches to synovial membrane volume determination by magnetic resonance imaging: manual versus automated segmentation. Br J Rheumatol 1997;36:1166–77. [DOI] [PubMed] [Google Scholar]
- 18. Ostergaard M, Stoltenberg M, Lovgreen-Nielsen P. et al. Magnetic resonance imaging-determined synovial membrane and joint effusion volumes in rheumatoid arthritis and osteoarthritis: comparison with the macroscopic and microscopic appearance of the synovium. Arthritis Rheum 1997;40:1856–67. [DOI] [PubMed] [Google Scholar]
- 19. Ostergaard M, Stoltenberg M, Lovgreen-Nielsen P. et al. Quantification of synovistis by MRI: correlation between dynamic and static gadolinium-enhanced magnetic resonance imaging and microscopic and macroscopic signs of synovial inflammation. Magn Reson Imaging 1998;16:743–54. [DOI] [PubMed] [Google Scholar]
- 20. Crema MD, Roemer FW, Li L. et al. Comparison between semiquantitative and quantitative methods for the assessment of knee synovitis in osteoarthritis using non-enhanced and gadolinium-enhanced MRI. Osteoarthritis Cartilage 2017;25:267–71. [DOI] [PubMed] [Google Scholar]
- 21. Kornaat PR, Bloem JL, Ceulemans RYT. et al. Osteoarthritis of the knee: association between clinical features and MR imaging findings. Radiology 2006;239:811–7. [DOI] [PubMed] [Google Scholar]
- 22. Peterfy CG, Guermazi A, Zaim S. et al. Whole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis. Osteoarthritis Cartilage 2004;12:177–90. [DOI] [PubMed] [Google Scholar]
- 23. Loeuille D, Chary-Valckenaere I, Champigneulle J. et al. Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imaging findings with disease severity. Arthritis Rheum 2005;52:3492–501. [DOI] [PubMed] [Google Scholar]
- 24. Roemer FW, Jarraya M, Felson DT. et al. Magnetic resonance imaging of Hoffa's fat pad and relevance for osteoarthritis research: a narrative review. Osteoarthritis Cartilage 2016;24:383–97. [DOI] [PubMed] [Google Scholar]
- 25. Roemer FW, Guermazi A, Zhang Y. et al. Hoffa's Fat Pad: evaluation on Unenhanced MR images as a measure of patellofemoral synovitis in osteoarthritis. AJR Am J Roentgenol 2009;192:1696–700. [DOI] [PubMed] [Google Scholar]
- 26. Hunter DJ, Guermazi A, Lo GH. et al. Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score). Osteoarthritis Cartilage 2011;19:990–1002. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Hunter DJ, Lo GH, Gale D. et al. The reliability of a new scoring system for knee osteoarthritis MRI and the validity of bone marrow lesion assessment: BLOKS (Boston Leeds Osteoarthritis Knee Score). Ann Rheum Dis 2008;67:206–11. [DOI] [PubMed] [Google Scholar]
- 28. Hodgson RJ, O'Connor P, Moots R.. MRI of rheumatoid arthritis image quantitation for the assessment of disease activity, progression and response to therapy. Rheumatology 2008;47:13–21. [DOI] [PubMed] [Google Scholar]
- 29. Arden NK, Cro S, Sheard S. et al. The effect of vitamin D supplementation on knee osteoarthritis, the VIDEO study: a randomised controlled trial. Osteoarthritis Cartilage 2016;24:1858–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Kellgren JH, Lawrence JS.. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957;16:494–502. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Perry TA, Gait A, O’Neill TW. et al. Measurement of synovial tissue volume in knee osteoarthritis using a semiautomated MRI-based quantitative approach. Magn Reson Med 2019;81:3056–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Roemer FW, Felson DT, Yang T. et al. The association between meniscal damage of the posterior horns and localized posterior synovitis detected on T1-weighted contrast-enhanced MRI–the MOST study. Semin Arthritis Rheum 2013;42:573–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33. Guermazi A, Roemer FW, Hayashi D. et al. Assessment of synovitis with contrast-enhanced MRI using a whole-joint semiquantitative scoring system in people with, or at high risk of, knee osteoarthritis: the MOST study. Ann Rheum Dis 2011;70:805–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34. Perry TA, Parkes MJ, Hodgson R. et al. Effect of Vitamin D supplementation on synovial tissue volume and subchondral bone marrow lesion volume in symptomatic knee osteoarthritis. BMC Musculoskelet Disord 2019;20:76. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35. Aguinis H, Gottfredson RK, Joo H.. Best-practice recommendations for defining, identifying, and handling outliers. Organi Res Methods 2013;16:270–301. [Google Scholar]
- 36. Fernandez-Madrid F, Karvonen RL, Teitge RA. et al. Synovial thickening detected by MR imaging in osteoarthritis of the knee confirmed by biopsy as synovitis. Magn Reson Imaging 1995;13:177–83. [DOI] [PubMed] [Google Scholar]
- 37. Gumpel JM, Matthews SA, Altman DG, Spencer JD, Wilkins EA.. An objective assessment of synovitis of the knee: measurement of the size of the suprapatellar pouch on xeroradiography. Ann Rheum Dis 1980;39:359–66. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Wang K, Ding C, Hannon MJ. et al. Signal intensity alteration within infrapatellar fat pad predicts knee replacement within 5years: data from the Osteoarthritis Initiative. Osteoarthritis Cartilage 2018;26:1345–50. [DOI] [PubMed] [Google Scholar]
- 39. Han W, Aitken D, Zhu Z. et al. Hypointense signals in the infrapatellar fat pad assessed by magnetic resonance imaging are associated with knee symptoms and structure in older adults: a cohort study. Arthritis Res Ther 2016;18:234. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40. Nielsen FK, Egund N, Peters D, Jurik AG.. Measurement of bone marrow lesions by MR imaging in knee osteoarthritis using quantitative segmentation methods–a reliability and sensitivity to change analysis. BMC Musculoskelet Disord 2014;15:447. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41. Nielsen FK, Egund N, Jorgensen A, Peters DA, Jurik AG.. Assessment of subchondral bone marrow lesions in knee osteoarthritis by MRI: a comparison of fluid sensitive and contrast enhanced sequences. BMC Musculoskelet Disord 2016;17:479. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated and analysed in this study are available upon reasonable request. Access to data generated in this report should be sent to the corresponding author at thomas.perry@ndorms.ox.ac.uk.