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Clinical and epidemiological research
Extended report
Association between MRI-detected knee joint regional effusion-synovitis and structural changes in older adults: a cohort study
  1. Xia Wang1,
  2. Leigh Blizzard1,
  3. Andrew Halliday2,
  4. Weiyu Han1,
  5. Xingzhong Jin1,
  6. Flavia Cicuttini3,
  7. Graeme Jones1,
  8. Changhai Ding1,3,4
  1. 1Menzies Research Institute Tasmania, University of Tasmania, Hobart, Tasmania, Australia
  2. 2Department of Radiology, Royal Hobart Hospital, Hobart, Tasmania, Australia
  3. 3Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
  4. 4Arthritis Research Institute, 1st Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
  1. Correspondence to Professor Changhai Ding, Menzies Institute for Medical Research, University of Tasmania; Private Bag 23, Hobart, Tasmania 7000, Australia; changhai.ding{at}utas.edu.au.

Abstract

Objective To describe the cross-sectional and longitudinal associations between knee regional effusion-synovitis and structural changes in older adults.

Methods A total of 977 subjects were randomly selected from the local community (mean 62 years, 50% female) at baseline and 404 were followed up 2.6 years later. T2-weighted MRI was used to assess knee effusion-synovitis in four subregions: suprapatellar pouch, central portion, posterior femoral recess and subpopliteal recess. Knee cartilage defects, cartilage volume and bone marrow lesions (BMLs) were measured using MRI at baseline and follow-up.

Results Cross-sectionally, effusion-synovitis in most subregions was significantly associated with a higher risk of cartilage defects, BMLs and reduced cartilage volume. Longitudinally, suprapatellar pouch effusion-synovitis at baseline predicted an increase in cartilage defects (p<0.01), loss of cartilage volume (p=0.04) and an increase in BMLs (p=0.02) in multivariable analyses. The significant associations of effusion-synovitis with cartilage volume and BMLs disappeared after adjustment for cartilage defects. Effusion-synovitis in whole knee joint (p<0.01) and subpopliteal recess (p<0.05) was consistently associated with longitudinal changes in cartilage defects but not in cartilage volume and BMLs.

Conclusions There are independent associations between knee joint effusion-synovitis and knee cartilage defects in both cross-sectional and longitudinal analyses, suggesting a potential causal relationship. The associations of effusion-synovitis with BMLs and cartilage volume were largely dependent on cartilage defects, suggesting potential causal pathways.

  • Knee Osteoarthritis
  • Synovitis
  • Inflammation

https://doi.org/10.1136/annrheumdis-2014-206676

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    Introduction

    Osteoarthritis (OA) is characterised by joint pain and structural changes including cartilage loss and subchondral bone abnormalities. Synovial activation, namely, proliferation and inflammation, has emerged as a critical component of OA and a potential predictor of disease progression.1 It has been linked to the signs of disease flare-up, such as joint swelling and inflammatory pain,2 though not all are consistent.3 ,4

    Synovial inflammation can occur at both the early and late stages of OA.5 In vitro and animal studies have demonstrated that inflamed synovium produces catabolic and pro-inflammatory mediators such as cytokines, nitric oxide, prostaglandin E2 and neuropeptides, which lead to excess production of the proteolytic enzymes responsible for cartilage breakdown, disturbing the homeostasis of cartilage matrix degradation and repair.6 ,7 Cartilage breakdown products in turn exacerbate synovial inflammation, creating a vicious circle.8 These suggest that synovial inflammation can be a cause or a result of knee structural changes; however, epidemiological and clinical studies have shown inconsistent associations between synovial inflammation and knee focal cartilage loss.9–11 It is not known whether synovial inflammation is associated with diffuse cartilage loss assessed by cartilage volume and subchondral bone abnormalities such as bone marrow lesions (BMLs), and whether synovial inflammation is causally related to these structural changes.

    Clinically, synovial pathology is usually manifested as thickening of synovium (synovitis) and/or excess synovial fluid (effusion),12 which are usually assessed as a whole according to the extent of capsular distention using non-contrast-enhanced MRI.13 To date, it is still unknown whether effusion/synovitis is distributed in a homogeneous fashion within the joint cavity. It is also unclear whether effusion/synovitis in different anatomical subregions have different impacts on intra-articular pathology. MRI is able to detect minor effusion/synovitis in the whole joint, which allows us to determine whether effusion/synovitis in different locations is associated with MRI-detected osteoarthritic alterations. The aim of this study, therefore, was to describe the cross-sectional and longitudinal associations between knee regional effusion-synovitis and structural changes in older adults.

    Subjects and methods

    Study design, setting and participants’ recruitment

    The Tasmania Older Adult Cohort study is a prospective, population-based cohort study, with a goal of identifying risk factors related to OA in older adults. Participants between the age of 50 and 80 years were randomly selected from the roll of electors in southern Tasmania (population 229 000) using sex-stratified random sampling. Participants who were institutionalised or had contraindications to MRI were excluded. Baseline (phase 1) data were collected from February 2002 to September 2004 in 1100 subjects. Participants who did not have MRI scan at baseline (phase 1) were excluded (n=124).

    Knee MRIs

    All the participants underwent MRI scans of the right knee with a 1.5 T whole-body magnetic resonance unit (Picker International, USA) with a commercial transmit/receive extremity coil. The MRI sequence protocol included a T1-weighted fat suppression three-dimensional (3-D) gradient-recalled acquisition in the steady state, flip angle 30°, repetition time 31 ms, echo time 6.71 ms, field of view 16 cm, 60 partitions, 512 × 512–pixel matrix, acquisition time 5 min 58 s, 1 acquisition; sagittal images were obtained at a partition thickness of 1.5 mm without a between-slice gap. It also included a T2-weighted fat-suppressed fast-spin echo, flip angle 90°, repetition time 3067 ms, echo time 112 ms, field of view 16 cm, 15 partitions, 228 × 256–pixel matrix; sagittal images were obtained at a slice thickness of 4 mm with a interslice gap of 0.5–1.0 mm.14

    Exposure: knee effusion-synovitis

    Knee synovial effusion-synovitis at baseline was assessed as the presence of intra-articular fluid-equivalent signal on T2-weighted MRI. We distinguished effusion-synovitis in the following four subregions according to the anatomy of the knee joint synovial cavity.15 They are: (1) suprapatellar pouch, extends superiorly from the upper surface of the patellar, between the posterior suprapatellar fat pad (quadriceps femoris tendon) and the anterior surface of the femur; (2) central portion, lies between the central femoral and tibial condyles, around the ligaments and menisci; (3) posterior femoral recess, lies behind the posterior portion of each femoral condyle and the deep surface of the lateral and medial heads of the gastrocnemius; (4) subpopliteal recess, lies posteriorly between the lateral meniscus and the popliteal tendon (figure 1). Effusion-synovitis in each subregion was scored individually according to Whole-Organ Magnetic Resonance Imaging Score (WORMS), grading collectively from 0 to 3 in terms of the estimated maximal distention of the synovial cavity: 0 refers to normal; 1 to <33% of maximum potential distention; 2 to 33%–66% of maximum potential distention; 3 to >66% of maximum potential distention.16 Pathological effusion-synovitis was defined as any score of ≥2 in each subregion.9 Total effusion-synovitis of the whole joint was defined as a score of ≥2 in any subregion. Two independent observers who scored images were blinded to the patients’ information. The intraclass reliability assessed as weighted κ in 50 randomly selected images was 0.63–0.75 in different subregions, and the interclass inter-rater reliability was 0.65–0.79 (0.6=threshold for good validity17).

    Figure 1
    Figure 1

    T2-weighted fat-saturation fast spin echo sagittal images for effusion-synovitis in different subregions. (A) Grade 3 effusion-synovitis in suprapatellar pouch (arrow) and grade 1 effusion-synovitis in central portion (arrow head); (B) Grade 3 effusion-synovitis around posterior cruciate ligament (arrow); (C-D) Grade 2 effusion-synovitis in posterior femoral recess (arrow) and subpopliteal recess (arrow), respectively.

    Outcomes: knee structural changes

    Baseline and follow-up knee cartilage volume at medial and lateral tibial and patellar sites was assessed on T1-weighted MRI, which was determined with image processing on an independent workstation using OsiriX software.18 The volumes of individual cartilage plates (medial tibial, lateral tibial and patellar) were isolated from the total volume by manually drawing disarticulation contours around the cartilage boundaries on a section-by-section basis. These data were then resampled by means of bilinear and cubic interpolation for the final three dimensional rendering. The coefficient of variation (CV) for this method was 2.1%, as described in our previous study.18 The rate of change in cartilage volume was calculated as follows: percentage change per annum (pa)=[(absolute change/baseline cartilage volume)/(time between two scans, in years)]×100.

    Cartilage defects at medial tibial, medial femoral, lateral tibial, lateral femoral and patellar sites were assessed at baseline and follow-up on the T1-weighted MRIs, using the modified Outerbridge Score (0–4)19 as follows: grade 0=normal cartilage; grade 1=focal blistering and intracartilaginous low-signal-intensity area with an intact surface; grade 2=irregularities on the surface or bottom and loss of thickness <50%; grade 3=deep ulceration with loss of thickness >50%; grade 4=full-thickness chondral wear with exposure of subchondral bone.18 The presence of cartilage defect was defined as a score of ≥2 at any site. The intraclass correlation coefficients (ICCs) for intraobserver and interobserver reproducibility were 0.85–0.93 and 0.89–0.94, respectively.18 An increase in the cartilage defect score from baseline to follow-up at any site was defined as a change of ≥1 on the five-point scale.

    Subchondral BMLs were assessed on the T2-weighted MRIs and defined as discrete areas of increased signal adjacent to the subcortical bone at the lateral, medial femur and/or tibia. Each BML was scored on the basis of lesion size as previously described.20 Intraobserver repeatability was assessed in 50 subjects between two readers with ICCs from 0.89 to 1.00 at different sites.20

    Tibial plateau bone area was defined as the cross-sectional surface area of the tibial plateau. Bone area was measured on three slices closest to the tibial cartilage, and the mean of all three areas was used as an estimate of the tibial plateau bone area. In a previous study, CVs were calculated in a range from 2.2% to 2.6%.14

    Meniscal lesions were assessed by a trained observer on MRIs as previously described.21 The proportion of the menisci affected by a tear, partial or full extrusion was scored laterally and medially at the anterior, middle and posterior horns. These scores were summed to create a total meniscal pathology score.

    Radiographs

    All participants underwent radiographic evaluation of the right knee at baseline. Each knee joint was scored for osteophytes and joint space narrowing (JSN), each on a scale of 0–3, according to the Osteoarthritis Research Society International atlas.22 All images were scored by two clinicians who were blinded to the patient information. A score of JSN or osteophytes of 2 or 3 was defined as moderate-to-severe JSN or osteophytes. The osteophytes and JSN scores were summed to produce a knee total radiographic OA (ROA) score. A total ROA score of 1 or greater is defined as presence of ROA.23 ICC was 0.99 for osteophytes and 0.98 for JSN as previously described.14

    Anthropometrics

    Height and weight were measured at the baseline clinic visit. Body mass index (BMI) was calculated as weight (in kg) divided by square of height (in m2).

    Statistical methods

    Comparisons of baseline characteristics by effusion-synovitis status were carried out using unpaired Student t tests or χ2 tests (as appropriate). The statistically significant differences between subjects who completed the study and who were lost to follow-up were evaluated using Student t test or χ2 tests (as appropriate).

    We examined the associations between effusion-synovitis and baseline/change in cartilage volume using linear regression. Logistic regression analysis and generalised linear models were used to estimate prevalence ratios (PRs) or relative risks (RRs)24 between effusion-synovitis and JSN, osteophytes, cartilage defects and BMLs. The associations were adjusted for age, gender, BMI and ROA, and further adjusted for tibial bone area (for cartilage volume), cartilage defects and/or BMLs (where appropriate). Standard diagnostic checks of model fit and residuals were routinely performed, and data points with large residuals and/or high influence were investigated for data errors. Interactions between gender or ROA, and effusion-synovitis were investigated by testing the statistical significance of the coefficient of a product term (effusion×gender or ROA) after adjustment for confounders. All statistical analyses were performed on Stata V.12.0 (Stata, College Station, Texas, USA). Statistical significance was set as a p value of ≤0.05 (two-tailed).

    Results

    At baseline, 977 subjects (50% females) were included in this study. The average age was 62.3 years, and the mean BMI was 27.7 kg/m2. Prevalence of knee joint effusion-synovitis (≥2) was 67% in the whole joint cavity (42.9% in suprapatellar pouch, 48.8% in central portion, 10.3% in posterior femoral recess and 14.4% in subpopliteal recess). As shown in table 1, participants with or without effusion-synovitis (score 0–1 vs 2–3) were similar in terms of gender, BMI, ROA, total cartilage volume and BMLs; however, participants with effusion-synovitis were older, had larger tibial bone size and had higher proportions with osteophytes and cartilage defects.

    View this table:
    Table 1

    Characteristics of sample at baseline

    Over 2.7 years (range from 1.3 to 4.8 years), 115 subjects did not continue at follow-up because of death (n=28), joint replacement (n=15), being physically unable (n=28), moving away (n=20) and other reasons such as refusing to continue or giving no reason. In subjects who completed the follow-up study, the first 404 subjects had the second MRI scan, but the others did not because the local MRI machine was decommissioned and became unavailable for research purposes. There were no significant differences in demographic factors, including age, gender, BMI and diseases status, between participants who remained in the study and who dropped out (data not shown). There were no significant interactions between demographic factors and effusion-synovitis on joint structural changes.

    Associations with cartilage defects

    Cross-sectionally, knee effusion-synovitis in all of the subregions, including suprapatellar pouch, central portion, posterior femoral recess and subpopliteal recess, was significantly associated with cartilage defects in multivariable analyses (table 2). The significant associations apart from that in central portion remained significant after further adjustment for BMLs (table 2).

    View this table:
    Table 2

    Associations between knee effusion-synovitis and cartilage defects

    Longitudinally, effusion-synovitis in whole knee joint, suprapatellar pouch and subpopliteal recess was significantly associated with worsening cartilage defects and remained significant after further adjustment for baseline BMLs and cartilage defects (table 2). There was a dose–response association between suprapatellar pouch effusion-synovitis and an increase in cartilage defects (figure 2A).

    Figure 2
    Figure 2

    Longitudinal associations between joint effusion-synovitis in suprapatellar pouch and structural measures over 2.6 years. (A) Increases in cartilage defects (%). (B) Changes in cartilage volume per annum (%). (C) Increases in bone marrow lesions (%). *p Values were those after adjustment for baseline age, gender, body mass index and radiographic osteoarthritis.

    Associations with cartilage volume

    Cross-sectionally, effusion-synovitis in whole joint, suprapatellar pouch and posterior femoral recess was negatively associated with total tibial and patellar cartilage volume after adjustment for age, gender, BMI, ROA, bone area and BMLs (table 3). These associations became non-significant after further adjustment for cartilage defects (table 3). Effusion-synovitis in central portion and subpopliteal recess was not significantly associated with total cartilage volume (table 3).

    View this table:
    Table 3

    Associations between knee effusion-synovitis and cartilage volume

    Longitudinally, effusion-synovitis in suprapatellar pouch was significantly associated with change in total tibial and patellar cartilage volume after adjustment for age, gender, BMI and ROA (table 3). Grades 2 and 3 suprapatellar pouch effusion-synovitis was associated with greater loss of cartilage volume than grade 1 effusion-synovitis (figure 2B). The magnitude of association decreased by 11% and became of borderline significance (p=0.07) after further adjustment for baseline cartilage volume, tibial bone area and BMLs (table 3) (decreased by 7% after sole adjustment for BMLs). The magnitude of association decreased by a further 17% after adjustment for cartilage defects (table 3). Effusion-synovitis in other subregions was not significantly associated with change in knee cartilage volume (table 3).

    Associations with BMLs

    As shown in table 4, in multivariable analyses, effusion-synovitis in most of the subregions (except posterior femoral recess) was significantly associated with BMLs at baseline, but became non-significant after further adjustment for cartilage defects.

    View this table:
    Table 4

    Associations between knee effusion-synovitis and bone marrow lesions

    After 2.6 years follow-up, only suprapatellar pouch effusion-synovitis was significantly associated with increases in BMLs after adjustment for age, gender, BMI and ROA and baseline BMLs (table 4). Grade 3 effusion-synovitis was significantly associated with greater increase in BMLs than grades 1 and 2 effusion-synovitis (figure 2C). The significant association disappeared after further adjustment for cartilage defects (table 4).

    Radiographic changes

    Radiographic changes including JSN and osteophytes were assessed cross-sectionally. The prevalence of ROA were 54% and 25% in the medial and lateral tibiofemoral compartments, respectively. Effusion-synovitis in the whole joint (PR: 1.36, 95% CI 1.12 to 1.66), suprapatellar pouch (PR: 1.44, 95% CI 1.20 to 1.71), posterior femoral recess (PR: 1.51, 95% CI 1.04 to 2.18) and subpopliteral recess (PR: 1.37, 95% CI 1.11 to 1.69) was significantly associated with greater moderate-to-severe JSN in multivariable analyses. Effusion-synovitis in the whole joint (PR: 1.58, 95% CI 1.07 to 2.35), suprapatellar pouch (PR: 1.97, 95% CI 1.38 to 2.81) and subpopliteral recess (PR: 1.53, 95% CI 1.00 to 2.34) was also significantly associated with osteophytes in multivariable analyses. All these significant associations disappeared after adjustment for cartilage defects, but remained largely unchanged after adjustment for BMLs (data not shown).

    Other analyses

    Meniscal lesions were assessed in 831 subjects at baseline and 314 subjects at follow-up (others not because the images were not clear enough for meniscal assessment). The associations between knee effusion-synovitis and structural changes remained largely unchanged after further adjustment for meniscal lesions in these samples (data not shown). We also investigated cross-sectional and longitudinal associations between regional effusion-synovitis and compartmental cartilage defects, cartilage volume and BMLs, and found no consistently site-specific associations (see online supplementary tables S1–S3). Neither in gender nor ROA subgroup analyses, significant differences were found in terms of the associations between effusion-synovitis and structural changes (data not shown).

    Discussion

    To the best of our knowledge, this is the first study to report the associations between subregional effusion-synovitis and multiple knee structural changes in older adults. Knee joint effusion-synovitis was associated cross-sectionally with increased knee cartilage defects, BMLs and reduced cartilage volume; and longitudinally, with increases in knee cartilage defects and BMLs, and a loss of cartilage volume. The longitudinal associations were observed mainly for the suprapatellar pouch, and, to a lesser extent, the subpopliteal recess, but not in posterior femoral recess and central portion. The significant associations with cartilage defects were independent of BMLs, but the associations with cartilage volume, BMLs and radiographic changes were largely mediated by cartilage defects. Our results suggest that knee effusion-synovitis, particularly in suprapatellar pouch, may be causally related to cartilage defects, which would lead to BMLs and cartilage loss over time.

    Previous assessment for effusion-synovitis was usually limited to the supraptellar pouch, but an anatomical atlas describes some relatively isolated synovial regions that lie within the knee joint cavity.15 ,25 In patients with traumatic injuries, 99% effusions were found in the central portion, 76% knees in the suprapatellar pouch with only 9% in the posterior femoral recess and 2% in subpopliteal recess.25 Using contrast-enhanced MRI, Roemer et al13 reported that the most common sites for synovitis were posterior to the posterior cruciate ligament (71.2%) and the suprapatellar region (59.5%). These were consistent with our findings that the prevalence of knee joint effusion-synovitis (≥2) was higher in the suprapatellar pouch and central portion and lower in the posterior femoral recess and subpopliteal recess. These regional separations allowed us to examine the anatomical patterns of synovial inflammation within the joint cavity, in order to investigate whether regional synovial inflammation has different effects on intra-articular pathology.

    So far, only a few studies have evaluated the roles of knee effusion and/or synovitis in knee osteoarthritic changes, and the findings were inconsistent. Hill et al11 reported that change in synovitis/effusion was associated with change in knee pain, but not with focal cartilage loss in patients with symptomatic OA. In a 30-month cohort study, Roemer et al10 found that synovitis or effusion might increase the risk of fast focal cartilage loss in 347 individuals who had or were at higher risk for knee OA, but the result was only of statistically borderline significance (p=0.07). This group also examined the associations between effusion-synovitis and focal cartilage loss in 514 subjects with neither cartilage damage nor ROA. They found that effusion-synovitis was associated with an increased risk for focal cartilage loss in tibiofemoral compartment but not patellofemoral compartment.9 These studies did not assess diffuse cartilage volume loss using quantitative MRI measurement, mostly assessed synovitis/effusion around the suprapatellar area and did not examine other structural changes such as BMLs.

    Using fat-suppressed T2-weighted MRI, we found that joint effusion-synovitis in suprapatellar pouch was consistently associated with focal (cartilage defects) and diffuse (reduced cartilage volume) cartilage loss in older adults both cross-sectionally and longitudinally, indicating that suprapatellar pouch effusion-synovitis may induce focal cartilage loss observed largely at an earlier stage as well as diffuse cartilage loss seen mainly at a later stage of OA. Effusion-synovitis per grade in suprapatellar pouch was associated with 13% increased prevalence and 19% increased incidence of cartilage defects, which are quite evident, considering that the overall prevalence of cartilage defect was 47% and incidence was 33% in this sample. These findings are clinically relevant and suggest that therapies aiming to reduce effusion-synovitis may slow disease progression of knee OA. The associations with cartilage volume loss decreased in magnitude by 17% after further adjustment for cartilage defects and by only 7% after adjustment for BMLs, suggesting that effects of effusion on cartilage volume loss are largely through cartilage defects.

    Additionally, our study explored the effects of effusion-synovitis in other subregions. We found that effusion-synovitis in subpopliteal recess was cross-sectionally and longitudinally associated with increased cartilage defects, but its association with cartilage volume loss was not significant. These indicated that subpopliteal recess effusion-synovitis might only cause focal cartilage loss. Furthermore, although effusion-synovitis in the central portion and posterior femoral recess was cross-sectionally associated with increased cartilage defects, no longitudinal associations were found, suggesting that effusion-synovitis in these two subregions might not play a significant role in inducing cartilage loss.

    BMLs have been reported to play a pivotal role in knee OA,26 ,27 but the causes of the marrow signal changes are still uncertain. Hypothetically, synovial fluid can be forced under pressure into the subchondral bone marrow through defects in cartilage or bone, increasing marrow fluid and eventual trabecular bone excavation, and thus cause BMLs, which is similar to the mechanism of cyst formation.28 Yet, there is only one cross-sectional study reporting that synovial membrane volume measured in contrast-enhanced MRI was significantly associated with volume of subcondral BMLs.29 Our study confirmed the significant cross-sectional associations between effusion-synovitis in most joint regions and BMLs, and was the first to report that longitudinal association between suprapatellar pouch effusion-synovitis and increases in BMLs over time. The significant associations disappeared after further adjustment for cartilage defects, indicating that joint effusion may lead to BMLs via cartilage defects. This would be consistent with our previous study where defects predicted BML worsening.30

    This study reported the most consistent associations between suprapatellar pouch effusion-synovitis and cartilage defects, cartilage volume loss and BML, suggesting this may be the most important site.31 It is possibly because suprapatellar pouch has the largest capacity to expand, but the spaces in the central portion and other regions are often limited by joint structures. Suprapatellar pouch effusion-synovitis was the most severe and this was why it was more frequently associated with cartilage loss. Effusion-synovitis in subpopliteal recess may also cause focal cartilage loss. Although effusion-synovitis in major subregions was associated with JSN and osteophytes, causal relationships are unclear due to the cross-sectional nature of these findings.

    The strengths of the present study lie in the comprehensive MRI and radiographic measurements and the effort taken to untangle site-specific and structural associations. There are several potential limitations in our study. First, loss of follow-up MRI caused by the reason as described earlier was high, but there were no differences in demographic factors between those who remained in the study and who dropped out. Second, we did not have radiographic assessments at follow-up, because X-ray is insensitive to detect the changes over this short period. Lastly, the prevalence of structure lesions such as BMLs (around 30%) in this sample was relatively small. However, this did not impact on our capacity to adjust for these putative structural covariates because doing so did not result in appreciable increase in the SEs of the principal study factor. In other words, we were adjusting for structural covariates without appreciable loss of precision.

    In conclusion, there are independent associations between knee joint effusion-synovitis and knee cartilage defects in both cross-sectional and longitudinal analyses, suggesting a potential causal relationship. The associations of effusion-synovitis with BMLs and cartilage volume were largely dependent on cartilage defects, suggesting potential causal pathways.

    Acknowledgments

    We especially thank the participants who made this study possible, and we gratefully acknowledge the role of the Tasmania Older Adult Cohort staff and volunteers in collecting the data, particularly research nurses Catrina Boon and Pip Boon. We also thank Dr Velandai Srikanth and Dr Helen Cooley, who assessed the radiographs.

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    Supplementary materials

    • Supplementary Data

      This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.

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    Footnotes

    • Handling editor Tore K Kvien

    • Contributors XW had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design: CD and GJ. Acquisition of data: XW and CD. Analysis and interpretation of data: XW, LB, XJ, WH, FC, GJ, and CD. Manuscript preparation and approval: XW, XJ, WH, HA, LB, FC, GJ and CD.

    • Funding This project was funded by the National Health and Medical Research Council of Australia (302204), the Tasmanian Community Fund (D0015018), the Arthritis Foundation of Australia (MRI06161) and the University of Tasmania Grant-Institutional Research Scheme (D0015019).

    • Competing interests None.

    • Patient consent Obtained.

    • Ethics approval The study was approved by the Southern Tasmania Health and Medical Human Research Ethics Committee, and written informed consent was obtained from all participants.

    • Provenance and peer review Not commissioned; externally peer reviewed.