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Clinical and epidemiological research
Extended report
Signal intensity alteration in the infrapatellar fat pad at baseline for the prediction of knee symptoms and structure in older adults: a cohort study
  1. Weiyu Han1,2,
  2. Dawn Aitken1,
  3. Zhaohua Zhu1,
  4. Andrew Halliday3,
  5. Xia Wang1,
  6. Benny Antony1,
  7. Flavia Cicuttini4,
  8. Graeme Jones1,
  9. Changhai Ding1,4,5
  1. 1Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia
  2. 2Department of Orthopaedics, 3rd Affiliated Hospital of Southern Medical University, Guangzhou, China
  3. 3Department of Radiology, Royal Hobart Hospital, Hobart, Tasmania, Australia
  4. 4Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia
  5. 5Arthritis Research Institute, 1st Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China
  1. Correspondence to Dr 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 associations between infrapatellar fat pad (IPFP) signal intensity alteration at baseline and knee symptoms and structural changes in older adults.

Methods A total of 874 subjects (mean 62.1 years, 50.1% female) selected randomly from local community were studied at baseline and 770 were followed up (only 357 had MRI at follow-up) over 2.6 years. T1-weighted or T2-weighted fat suppressed MRI was used to assess IPFP signal intensity alteration (0–3), cartilage volume, cartilage defects and bone marrow lesions (BMLs) at baseline and 2.6 years later. Knee pain was assessed by self-administered Western Ontario and McMaster Osteoarthritis Index questionnaire. Radiographic osteoarthritis (OA) was assessed.

Results In cross-sectional analyses, IPFP signal intensity alteration was significantly and positively associated with total knee pain as well as knee cartilage defects, BMLs and knee radiographic OA and negatively associated with patellar cartilage volume after adjustment for age, sex, body mass index and/or radiographic OA. Longitudinally, baseline signal intensity alteration within IPFP was significantly and positively associated with increases in knee pain when going upstairs/downstairs as well as increases in tibiofemoral cartilage defects and BMLs, and negatively associated with change in lateral tibial cartilage volume in multivariable analyses.

Conclusions IPFP signal intensity alteration at baseline was associated with knee structural abnormalities and clinical symptoms cross-sectionally and longitudinally in older adults, suggesting that it may serve as an important imaging biomarker in knee OA.

  • Inflammation
  • Magnetic Resonance Imaging
  • Knee Osteoarthritis

https://doi.org/10.1136/annrheumdis-2015-208360

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    Introduction

    Osteoarthritis (OA) is one of the most common diseases and is a leading cause of chronic disability in older adults.1 It not only affects the articular cartilage and subchondral bone but also involves other structures of the joint, including menisci, synovial membrane, joint capsule, ligaments, muscles and infrapatellar fat pad (IPFP).2 ,3

    Obesity has been considered as the primary preventable risk factor for OA,4 ,5 despite that the underlying mechanisms are not very clear. Obesity-related factors can induce pro-inflammatory cytokines and degradative enzymes, which lead to cartilage matrix impairment and subchondral bone remodelling,6 suggesting that adipose tissue may act through its metabolic properties. IPFP, a local adipose tissue, has been considered as an active joint tissue in knee OA.7 A recent review paper suggested that it would play an important role in knee OA.8 Although the mechanisms of IPFP in pathological processes of knee OA are largely unknown, biomechanical and biochemical pathways may be involved.9 ,10 Biomechanically, IPFP may reduce the impact loading and absorb forces generated through the knee joint, and thus may play a beneficial role in knee OA. Biochemically, abnormal IPFP can produce various pro-inflammatory cytokines such as interleukin (IL)-1β, tumour necrosis factor (TNF)-α, IL-6 and IL-8, as well as various adipokines such as leptin and resistin,11–14 and thus may play a detrimental role in knee OA.

    IPFP signal intensity alteration can be observed in knee OA patients using T2-weighted or proton-density-weighted MRI.15 Although IPFP signal intensity alteration was considered as a non-specific feature, several clinical and epidemiological studies have used it as a surrogate for peripatellar synovitis.16 ,17 This type of synovitis within IPFP predicted the development of incident of radiographic OA (ROA).18 A pathological study showed there were vascular neoformations, fibrosis and inflammatory infiltrates in IPFP specimens obtained from patients with end-stage OA;19 therefore, IPFP signal intensity alteration observed in MRI may be related to not only synovitis but also other pathological changes. So far there are few studies focusing on the association between IPFP signal intensity alteration and knee symptom and structural changes, so it is unclear whether IPFP signal intensity alteration is an important surrogate marker in knee OA. The aim of this study was, therefore, to determine the associations between IPFP signal intensity alteration at baseline and knee symptoms or joint structural changes in older adults with or without knee OA.

    Materials and methods

    Subjects

    This study was conducted as part of the Tasmanian Older Adult Cohort study, an ongoing prospective, population-based study, with a goal of identifying the environmental, genetic and biochemical factors associated with the development and progression of OA. Participants (age 50–80 years) were selected and followed up over 2.7 years (range 2.6–3.3 years) as described previously.9 ,20 Institutionalised persons and subjects with contraindications to MRI and diagnosed rheumatoid arthritis were excluded. This study consisted of a consecutive sample of 874 participants who had knee MRI scans at baseline.

    Anthropometrics and WOMAC pain assessment

    Height and weight were measured as described previously.9 ,20 Body mass index (BMI, weight (kg)/height (m2)) was calculated.

    The assessment of knee pain (pain walking on a flat surface, going upstairs/downstairs, at night while in bed, sitting or lying, and standing upright) at baseline and follow-up was self-administered using the Western Ontario and McMaster Osteoarthritis Index (WOMAC) with a 10-point scale from 0 (no pain) to 9 (most severe).21 Each component score was summed to create a total score for knee pain (0–45), and the presence of knee pain was defined as a total score or a subscale score of ≥1. We have calculated the smallest statistically significant difference for WOMAC knee pain score to be 0.9 for our population, so an increase in pain was defined as a change in score of ≥1.22

    Knee radiographic assessment

    A standing anteroposterior semiflexed view of the right knee with 15° of fixed knee flexion at baseline was performed in all subjects, and joint space narrowing (JSN) and osteophytes on radiographs were individually assessed by two observers simultaneously on a scale of 0–3 (0=normal and 3=most severe).9 ,23 Disagreements in scoring were resolved by consensus with a third observer. The osteophytes and JSN scores were summed as the knee total ROA score, in which ≥1 was used to define the presence of knee ROA.24

    MRI assessment

    MRI scans of the right knees were performed at baseline and follow-up. Knees were imaged in the sagittal plane on a 1.5-T whole-body magnetic resonance unit (Picker, Cleveland, Ohio, USA) with use of a commercial transmit-receive extremity coil. The T1-weighted fat saturation 3D gradient recall acquisition and T2-weighted fat saturation 2D fast spin echo sequences were used as described previously.9 ,20

    IPFP signal intensity alteration at baseline and follow-up was assessed by an experienced orthopaedist (WH) trained by an experienced radiologist (AH), using T2-weighted MRIs (figure 1). Signal intensity alteration, defined as discrete areas of increased signal within IPFP, was graded as follows: grade 0=none; grade 1=<10% of the region; grade 2=10–20% of the region; grade 3=>20% of the region. Intraobserver and interobsever reliabilities (conducted by WH and ZZ) were assessed in 100 subjects with an intraclass correlation coefficient of 0.90 and an interclass correlation coefficient of 0.89, respectively.

    Figure 1
    Figure 1

    Sagittal T2-weighted images with fat saturation. (A) Normal infrapatellar fat pad (IPFP); (B) arrow indicates signal intensity alteration of IPFP (grade 1); (C) arrow points to signal intensity alteration of IPFP (grade 2); (D) arrow indicates signal intensity alteration of IPFP (grade 3).

    Knee cartilage volume at baseline and follow-up was assessed on T1-weighted MRIs with image processing on an independent workstation, as previously described.25–27 The total cartilage volume was divided into patellar, medial and lateral tibial cartilage volume.25 ,26 The coefficients of variation for this method in our hands were 2.1–2.6%.25 ,26 Changes in cartilage volume were calculated as: percentage change per annum=[(follow-up volume−baseline volume)/baseline cartilage volume]/time between 2 scans in years×100.

    Cartilage defects (0–4 scale) at baseline and follow-up were determined at the medial tibial, medial femoral, lateral tibial, lateral femoral and patellar sites as previously described.28 ,29 The presence of cartilage defects was defined as a cartilage defect score of ≥2 at any site. Intraobserver reliabilities were 0.89–0.94, and interobserver reliabilities were 0.85–0.93.28 An increase in cartilage defects was defined as a change in cartilage defects of ≥1.

    Subchondral bone marrow lesions (BMLs) at baseline and follow-up were defined as discrete areas of increased signal adjacent to the subcortical bone at the medial and lateral tibia and femur on T2-weighted MRIs using a semi-quantitative (0–3) scoring system.9 The intraobserver reliability ranged between 0.89 and 1.00.30 An increase in BMLs was defined as a change in BMLs of ≥1.

    Tibial plateau bone area at baseline was determined by manually measuring on axial T1-weighted MRIs, as previously described.24

    Data analysis

    Student's t or χ2 tests were used to compare means or proportions, respectively. Multivariable linear regression analyses were used to examine the associations between IPFP signal intensity alteration (independent variable) and knee cartilage volume or change in cartilage volume (dependent variables) after adjustment for age, sex, BMI, ROA and tibial bone area. Multivariable binary logistic regression analyses were used to examine the associations between IPFP signal intensity alteration (independent variable) and knee JSN, osteophytes, as well as baseline or increases in knee cartilage defects, BMLs and knee pain (dependent variables), after adjustment for age, sex, BMI and/or ROA. Interactions between ROA status and IPFP signal intensity alteration on the outcome measures were investigated by regressing individual change in an outcome on a binary (0/1) term for ROA within IPFP signal intensity alteration and assessed by testing the statistical significance of the coefficient of a (sex×IPFP signal intensity alteration).

    A p value<0.05 (two-tailed) or a 95% CI not including the null point (for linear regression) or 1 (for logistic regression) was considered as statistical significance. All statistical analyses were performed on SPSS V.20.0 for Windows (SPSS, Chicago, Illinois, USA).

    Results

    A total of 874 subjects between 50 and 80 years of age (mean, 62.1 years) took part in the present study. There were no significant differences in demographic factors (age, sex and BMI) between these participants and those excluded (n=226) (data not shown). Over 2.6 years, 104 subjects were lost to follow-up study due to 25 deceased, 18 moved to other states or overseas, 12 had joint replacement, 24 physically unable, and others refused or no reason. The remaining 770 subjects completed the follow-up study; however, MRI scans were only performed on 357 of these due to decommissioning of the MRI scanner during the study. There were no significant differences in terms of age (62.5 vs 61.9 years, p=0.779), female sex (50.7% vs 49.7%, p=0.783), BMI (27.6 vs 27.8, p=0.105) and ROA (57.2% vs 60.1%, p=0.426) between these subjects and those without follow-up MRI.

    Characteristics of the study population (n=874) are presented in table 1. The subjects with IPFP signal intensity alteration were older, had a higher prevalence of BMLs, lateral tibiofemoral and patellar cartilage defects, and greater tibial cartilage volume and tibial bone area than those without IPFP signal intensity alteration. A greater proportion were men in those with IPFP signal intensity alteration. Additionally, subjects with IPFP signal intensity alteration had a greater proportion of ROA, but it was of borderline significance. There was no significant difference in BMI, patellar cartilage volume, JSN, osteophytes, WOMAC knee pain and medial tibiofemoral cartilage defects between two groups. Characteristics of the participants with complete MRI data at follow-up (n=357) are also presented in online supplementary table S1.

    View this table:
    Table 1

    Baseline characteristics of participants based on IPFP signal intensity alteration

    Cross-sectionally, IPFP signal intensity alteration was significantly and positively associated with cartilage defects in univariable analyses and these associations remained significant after adjustment for age, sex, BMI and ROA (table 2). Longitudinally, baseline IPFP signal intensity was significantly and positively associated with increases in cartilage defects at medial and lateral tibiofemoral compartments in unadjusted (see online supplementary figure S1) and multivariable analyses (table 2). It was not significantly associated with an increase in patellar cartilage defects (table 2).

    View this table:
    Table 2

    Associations of baseline infrapatellar fat pat (IPFP) signal intensity alteration with baseline and changes in knee cartilage defects

    Cross-sectionally, IPFP signal intensity alteration was significantly and positively associated with BMLs in univariable and multivariable analyses (table 3). Longitudinally, baseline IPFP signal intensity alteration was significantly and positively associated with increases in BMLs at all sites before (see online supplementary figure S2) and after adjustment for age, sex, BMI and ROA (table 3).

    View this table:
    Table 3

    Associations of baseline infrapatellar fat pat (IPFP) signal intensity alteration with baseline and changes in bone marrow lesions

    In cross-sectional analyses, IPFP signal intensity alteration was significantly and positively associated with medial and lateral tibial cartilage volume, but not significantly associated with patellar cartilage volume. After adjustment for age, sex, BMI, ROA and tibial bone area, IPFP signal intensity alteration was not significantly associated with medial and lateral cartilage volume, but was significantly and negatively associated with patellar cartilage volume (table 4). The large reductions in the coefficients were largely due to adjustment for tibial bone area (data not shown). Longitudinally, baseline IPFP signal intensity alteration was not significantly associated with changes in cartilage volume at all sites in univariable analyses. After adjustment for covariates, it was negatively and significantly associated with change in lateral tibial cartilage volume, but not with changes in medial tibial and patellar cartilage volume (table 4).

    View this table:
    Table 4

    Associations of baseline infrapatellar fat pat (IPFP) signal intensity alteration with baseline and changes in knee cartilage volume

    In cross-sectional analyses, IPFP signal intensity alteration was significantly and positively associated with prevalence of total knee pain, pain when going upstairs/downstairs, and pain at night while in bed in univariable analyses. These associations remained, and the association with pain when sitting/lying became significant after adjustment for age, sex, BMI and ROA (table 5). These associations were similar when using knee pain scores as continuous variables (data not shown). Longitudinally, baseline IPFP signal intensity alteration was only significantly associated with an increase in pain when going upstairs/downstairs in univariable and multivariable analyses (see online supplementary figure S3 and table 5).

    View this table:
    Table 5

    Association of baseline infrapatellar fat pat (IPFP) signal intensity alteration with baseline and increases in Western Ontario and McMasters osteoarthritis index (WOMAC) knee pain

    In cross-sectional analyses, IPFP signal intensity alteration was significantly and positively associated with ROA (OR 1.23, p<0.05), tibiofemoral osteophytes (OR 1.64 and 1.74, respectively, for medial and lateral compartments; both p<0.05), but not with JSN, after adjustment for age, sex and BMI.

    Change in IPFP signal intensity score was positively and significantly associated only with change in cartilage defects in lateral tibiofemoral compartment (OR 1.41, 95% CI 1.06 to 1.87), but not with changes on other structural measures (data not shown). No significant interactions between ROA status and IPFP signal intensity alteration on the outcome measures were found (data not shown), so we combined subjects with and without ROA for all analyses.

    Discussion

    Although there were several studies using IPFP signal intensity alteration as a surrogate for peripatellar synovitis in patients with knee OA,16–18 this is a comprehensive cohort study to investigate the association of baseline IPFP signal intensity alteration with knee structure changes assessed by MRI and symptoms in older adults. We found that, cross-sectionally, IPFP signal intensity alteration was associated with increased knee symptoms, cartilage defects, BMLs and ROA, and with reduced patellar cartilage volume. Longitudinally, higher IPFP signal intensity alteration score at baseline predicted more increases in tibiofemoral cartilage defects and BMLs, greater loss of lateral tibial cartilage volume and more increases in knee symptoms. Our findings suggest that IPFP signal intensity alteration may play an important role in knee osteoarthritic changes in older adults.

    Although the exact function of IPFP in knee joint is unknown, it has been considered as an active OA joint tissue7 and may play an important role in knee OA.8 As a component of the enthesis organ in anterior knee region,31 IPFP may help to reduce stress at attachment sites and assist in decreasing shearing forces between adjacent structures,32 and indeed, our recent study33 reported that larger IPFP size was associated with reduced knee pain, MRI-assessed structural pathology and ROA, suggesting a potentially protective effect of IPFP size. Previous studies focusing on its biochemical components have indicated different roles of IPFP in OA processes. Bastiaansen-Jenniskens et al10 reported that fat-conditioned medium derived from IPFP of end-stage OA inhibited catabolic processes in cartilage. Ushiyama et al34 reported that IPFP obtained from patients during knee surgery contained protein levels of basic fibroblast growth factor, vascular endothelial growth factor (VEGF), TNF-α and IL-6 in homogenised tissues. Klein-Wieringa et al11 reported that IPFP from patients with primary OA secreted higher levels of IL-6, adipsin, adiponectin and visfatin than subcutaneous adipose tissue from the same patients. Based on the above evidence, we conjecture that IPFP would have biphasic effects in knee OA: it may play a beneficial role physiologically (through increased size) largely due to its biomechanical or anticatabolic properties but could also be detrimental pathologically (observed as signal intensity alteration on MRI) due to its pro-inflammatory or metabolic properties.

    IPFP signal intensity alterations can be detected using T2-weighted fast spin echo MRI. Although this signal intensity alteration has been recognised as a non-specific feature in MRI, it was used as a surrogate for peripatellar synovitis in some clinical and epidemiological studies,16 ,17 and Hoffa-synovitis has been associated with incident ROA.18 This assessment was sensitive but not specific for synovitis.35 Pathological evidence has indicated that IPFP signal intensity alteration may represent a multitude of conditions such as chronic inflammation, vascular neoformations and oedema rather than only synovitis.19 So far, there are no direct comparisons between IPFP signal intensity alteration within whole IPFP and pathological changes in knee OA.

    Knee cartilage loss is the hallmark of OA. Inflammatory and metabolic factors, such as IL-6, TNF-α, basic fibroblast growth factor and leptin, have been involved in cartilage breakdown and eventually cartilage loss.36 ,37 IPFP is the main resource of these factors, and thus could have a role to play in the degradation of articular cartilage. Our current study reported that IPFP signal intensity alteration was independently associated with focal cartilage loss observed as knee cartilage defects but inconsistently with loss of entire cartilage plates (assessed using cartilage volume). These findings suggest that IPFP signal intensity alteration may precede focal cartilage defects.

    BMLs and osteophytes are the commonest subchondral bone abnormalities in knee OA. Both are associated with knee pain, cartilage defects and cartilage loss, and predict total knee replacement.38–40 In this study, we found that IPFP signal intensity alteration was positively and consistently associated with BMLs and knee osteophytes at baseline, and also predicted increases in BMLs in all compartments over 2.6 years, suggesting that pathological changes in IPFP may affect subchondral bone abnormalities. Some biochemical and biomechanical factors would underlie this association. Leptin and VEGF have been shown to promote osteophytes formation.41 ,42

    Knee pain is an important clinical outcome in knee OA. Some preliminary studies reported that signs of inflammation in IPFP (assessed using dynamic contrast-enhanced MRI) were cross-sectionally associated with knee pain in obese patients with knee OA,43 and inflammation and oedema of IPFP contributed to knee pain43 ,44 Oedema within IPFP could increase pressure and lead to irritation of nearby tissues such as knee capsule and nociceptive nerve fibres that contain substance-P,45 ,46 resulting in increased knee pain. Our current study reported that, cross-sectionally, IPFP signal intensity alteration was positively associated with knee pain (especially when going upstairs/downstairs, at night while in bed and when sitting or lying). Over 2.6 years, IPFP signal intensity alteration was only associated with an increase in knee pain when going upstairs/downstairs. Our results suggest that IPFP signal intensity alteration may play an important role in knee pain.

    The main strength of this cohort study is that we selected participants randomly from the community with a large sample size and both structural and symptomatic measurements. This study has several potential limitations. First, the response rate at baseline was 57%, possibly due to the extensive protocol, which did leave the possibility open for selection bias. However, there were no significant differences in age, gender and BMI between those that responded and those that did not. We also had high rates of retention (with the follow-up visit completed, 88%) to offset this. Second, although the retention rate at follow-up was high, these participants only completed WOMAC questionnaires and there were 59% subjects who did not have follow-up MRIs. However, there were no significant differences in baseline characteristics between those with and without follow-up MRI. Third, radiographs were not performed at the 2.7-year follow-up, so we were unable to determine the association between IPFP quality and change in ROA. Fourth, histological examinations were not able to perform in our study. Fifth, we used a change in knee pain score of ≥1 to define an increase in knee pain, which may not be sensitive for our tested hypothesis; however, multiple sensitivity analyses suggested that this definition is the most appropriate. We also used pain sore ≥1 to define presence of knee pain, which may not be the most clinically relevant, but the associations remained similar while using knee pain scores as continuous variables or defining prevalent knee pain using different cutpoints. Sixth, subjects with ROA (>50%) were included in the study and IPFP signal intensity could be a consequence of ROA; however, all the associations were adjusted for ROA and there were no significant interactions between ROA and IPFP signal intensity on the outcome measures, suggesting our findings were not influenced by ROA status. Last, measurement error may influence results. However, all measures were highly reproducible, suggesting this is unlikely.

    In conclusion, baseline IPFP signal intensity alteration was associated with knee structural abnormalities and clinical symptoms cross-sectionally and longitudinally in older adults, suggesting that it may be an important imaging biomarker in knee OA.

    Acknowledgments

    The authors thank the participants, who made this study possible, and acknowledge the role of the staff and volunteers in collecting the data, particularly research nurses Boon C and Boon P. Warren R assessed MRIs, and Dr Srikanth V and Dr Cooley H assessed radiographs.

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    View Abstract

    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.

    Footnotes

    • Handling editor Tore K Kvien

    • Contributors CD had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study design: CD, FC and GJ; Acquisition of data: WH, ZZ, AH, BA, XW, DA, GJ and CD; Analysis and interpretation of data: WH, AH, FC, GJ and CD; Manuscript preparation: WH, ZZ, AH, XW, BA, DA, GJ and CD; Statistical analysis: WH, ZZ, DA, XW, FC and CD.

    • Funding This study was supported by the National Health and Medical Research Council of Australia (302204); Arthritis Foundation of Australia (MRI06161); Tasmanian Community Fund (D0015018); Masonic Centenary Medical Research Foundation; Royal Hobart Hospital Research Foundation; and University of Tasmania Institutional Research Grants Scheme (D0015019).

    • Competing interests GJ is supported by a National Health and Medical Research Council Practitioner Fellowship. CD is supported by an Australian Research Council Future Fellowship. DA is supported by a National Health and Medical Research Council Early Career Fellowship.

    • Patient consent Obtained.

    • Ethics approval Southern Tasmanian Health and Medical Human Research Ethics Committee.

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