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The importance of synovial inflammation in osteoarthritis: current evidence from imaging assessments and clinical trials

  • X. Wang
    Affiliations
    Rheumatology Department, Royal North Shore Hospital and Institute of Bone and Joint Research, Kolling Institute, University of Sydney, St. Leonards, New South Wales, Australia
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  • D.J. Hunter
    Affiliations
    Rheumatology Department, Royal North Shore Hospital and Institute of Bone and Joint Research, Kolling Institute, University of Sydney, St. Leonards, New South Wales, Australia
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  • X. Jin
    Affiliations
    National Drug and Alcohol Research Centre, University of New South Wales, Randwick, New South Wales, Australia
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  • C. Ding
    Correspondence
    Address correspondence and reprint requests to: C. Ding, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China.
    Affiliations
    Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia

    Translational Research Centre, Academy of Orthopedics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
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Open ArchivePublished:December 07, 2017DOI:https://doi.org/10.1016/j.joca.2017.11.015

      Summary

      Synovial abnormalities have been observed at multiple stages of osteoarthritis (OA). Increasing evidence suggests that it may play an important role in the OA pathological process. Many assessment systems using magnetic resonance imaging (MRI) and ultrasound have been established to detect synovial inflammation in OA. These have been used to inform the current investigation of OA disease phenotypes and progression and can be utilised in the future for clinical trials developing potential treatments. This narrative review aims to illustrate the importance of synovial tissue in OA and provide an overview of imaging assessments and possible therapies targeting synovial abnormalities.

      Keywords

      Introduction

      OA is one of the leading causes of impaired mobility among older adults, characterised by pain and declining physical function
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      The effects of specific medical conditions on the functional limitations of elders in the Framingham Study.
      and in some cases, will lead to joint replacement. The 2015 Global Burden of Disease Study reports that OA is the most notable non-communicable disease with total disability-adjusted life-years (DALYs) rising by 35% between 1990 and 2015
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      . Risk factors such as age, female sex, obesity, injury, muscle weakness and malalignment contribute to the onset and progression of OA
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      Risk factors and prognostic factors of hip and knee osteoarthritis.
      . Evidence also suggests that metabolic dysfunction contributes to forming a potential OA phenotype, sharing a similar aetiology as obesity and diabetes
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      Metabolic triggered inflammation in osteoarthritis.
      .
      It is increasingly recognised that OA affects all structures within the joint via multiple causal pathways
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      Osteoarthritis: a disease of the joint as an organ.
      . Cartilage and subchondral bone are susceptible to abnormal external mechanical stress and internal biochemical or morphological changes, thus losing the function of absorbing biomechanical forces. Similarly, muscles, ligaments and menisci can fail due to injury or weakness, causing a breakdown in function and amplification of physical stresses. Notably, the synovium in OA can exhibit inflammatory responses, which further damage surrounding tissues through the release of pro-inflammatory mediators into the synovial fluid
      • Conaghan P.G.
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      MRI and non-cartilaginous structures in knee osteoarthritis.
      . This interdependence among tissues underpins the multifactorial nature of the disease, with the loss of normal function in one tissue directly influencing another. Thus, OA rarely has a single cause and often presents a variety of pathological features and symptoms.
      A number of recent clinical studies have considered abnormal synovial changes as one of the characteristic features in OA onset and progression assessed using contrast-enhanced (CE)
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      • Roemer F.W.
      • Li L.
      • Alexander R.C.
      • Chessell I.P.
      • Dudley A.D.
      • et al.
      Comparison between semiquantitative and quantitative methods for the assessment of knee synovitis in osteoarthritis using non-enhanced and gadolinium-enhanced MRI.
      or non-CE magnetic resonance imaging (MRI) sequences as well as ultrasound
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      • Belitskaya-Levy I.
      • Bencardino J.
      • Samuels J.
      • Attur M.
      • Regatte R.
      • et al.
      Quantitative magnetic resonance imaging evidence of synovial proliferation is associated with radiographic severity of knee osteoarthritis.
      • Hall M.
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      Synovial pathology detected on ultrasound correlates with the severity of radiographic knee osteoarthritis more than with symptoms.
      . This evidence supports the idea that the pathogenesis of OA may involve an active inflammatory process in some patients and an appropriate synovitis measure would have great value in differentiating a potential inflammatory phenotype. Also, data from several randomised controlled trials (RCTs) have detected significant synovial response following intra-articular steroid injection
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      • Hensor E.M.
      • Wakefield R.J.
      • Mease P.J.
      • Bingham 3rd, C.O.
      • Conaghan P.G.
      Ultrasound assessment of response to intra-articular therapy in osteoarthritis of the knee.
      • Maricar N.
      • Callaghan M.J.
      • Felson D.T.
      • O'Neill T.W.
      Predictors of response to intra-articular steroid injections in knee osteoarthritis–a systematic review.
      . Those data serve as critical evidence that synovial measures could be key outcomes in future clinical trials.
      The current narrative review, covers the period from January 2012 until October 2017, was based on PubMed with the following search terms applied in various arrangements: “synovitis”, “effusion”, “radiography”, “MRI,” “ultrasound” “osteoarthritis” and “clinical trials”. Because of the large number of publications, we selected papers in English with relevance to the knee, hip and hand joints and attempted to include updates on imaging used in synovial tissue assessments.

      Clinical impact of synovial inflammation in OA

      Physical function

      The normal synovium provides a deformable packing that allows movement of adjacent non-deformable tissues. Composed of thin connective tissue, it includes the continuous surface layer of cells (intima) and the underlying tissue (subintima)
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      • Heck D.A.
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      Synovial inflammation in patients with early osteoarthritis of the knee.
      . The intima consists of macrophages and fibroblasts while the subintima includes blood, lymphatic vessels and nerve fibres. The microscopic anatomy of normal synovial tissue often falls into three main types based on the content of the subintimal layer: fibrous, areolar and adipose
      • Smith M.D.
      Suppl 1: The Normal Synovium.
      . These structures have specialised viscoelastic properties for coping with the stretching, rolling and folding during joint movement
      • Tiwari N.
      • Chabra S.
      • Mehdi S.
      • Sweet P.
      • Krasieva T.B.
      • Pool R.
      • et al.
      Imaging of normal and pathologic joint synovium using nonlinear optical microscopy as a potential diagnostic tool.
      . Furthermore, the cellular elements of the synovium are responsible for the secretion of the viscid synovial fluid, which lubricates and nourishes the joint. The fluids also have a role in the removal of metabolic wastes and intra-articular particulate matter (e.g., cartilaginous debris), which could be diffused in the fluid or deposited within the membrane
      • Smith M.D.
      Suppl 1: The Normal Synovium.
      .
      Excess synovial fluid (effusion) may result from mechanical irritation by worn cartilage and bone, with the normal composition of the synovial fluid and excessive production of hyaluronic acid (HA) by intimal fibroblasts stimulated by frictional forces, such as in OA
      • Smith M.D.
      Suppl 1: The Normal Synovium.
      . Joint effusion in an inflammatory synovitis is likely to be an accumulation of exudate similar to the pleural effusion, for example, an overspill from the inflammatory edema in synovial tissue created by increased vascular permeability
      • Ropes M.W.
      • Rossmeisl E.C.
      • Bauer W.
      The origin and nature of normal human synovial fluid.
      .

      Association with symptoms

      Despite different approaches employed for detection and characterisation of synovitis (e.g., imaging or histologic assessment), solid evidence underpins the association between synovial inflammation and symptoms in patients with knee OA
      • Garnero P.
      • Piperno M.
      • Gineyts E.
      • Christgau S.
      • Delmas P.
      • Vignon E.
      Cross sectional evaluation of biochemical markers of bone, cartilage, and synovial tissue metabolism in patients with knee osteoarthritis: relations with disease activity and joint damage.
      . Torres et al. investigated the relationship between knee pain and specific joint pathology detected by MRI in OA patients. They noted that synovitis or effusion and bone marrow lesions (BMLs), were highly correlated with knee pain measured on a visual analog scale (VAS)
      • Torres L.
      • Dunlop D.
      • Peterfy C.
      • Guermazi A.
      • Prasad P.
      • Hayes K.
      • et al.
      The relationship between specific tissue lesions and pain severity in persons with knee osteoarthritis.
      . Others specifically examined the relationship between pain and MRI-detected synovitis and noted that changes in pain scores over time varied with changes in effusion and synovitis, strengthening the notion of a relationship
      • Wang X.
      • Jin X.
      • Han W.
      • Cao Y.
      • Halliday A.
      • Blizzard L.
      • et al.
      Cross-sectional and longitudinal associations between knee joint effusion synovitis and knee pain in older adults.
      • Lo G.H.
      • McAlindon T.E.
      • Niu J.
      • Zhang Y.
      • Beals C.
      • Dabrowski C.
      • et al.
      Bone marrow lesions and joint effusion are strongly and independently associated with weight-bearing pain in knee osteoarthritis: data from the osteoarthritis initiative.
      • Zhang Y.
      • Nevitt M.
      • Niu J.
      • Lewis C.
      • Torner J.
      • Guermazi A.
      • et al.
      Fluctuation of knee pain and changes in bone marrow lesions, effusions, and synovitis on magnetic resonance imaging.
      . Furthermore, there was a 9-fold greater risk of having painful knee OA conferred by higher grades of synovitis using contrast enhanced (CE)-MRI
      • Hill C.L.
      • Hunter D.J.
      • Niu J.
      • Clancy M.
      • Guermazi A.
      • Genant H.
      • et al.
      Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis.
      • Baker K.
      • Grainger A.
      • Niu J.
      • Clancy M.
      • Guermazi A.
      • Crema M.
      • et al.
      Relation of synovitis to knee pain using contrast-enhanced MRIs.
      . The independent associations between effusion-synovitis and knee symptoms in early OA highlighted it could trigger symptoms regardless of other structural abnormalities
      • Wang X.
      • Jin X.
      • Han W.
      • Cao Y.
      • Halliday A.
      • Blizzard L.
      • et al.
      Cross-sectional and longitudinal associations between knee joint effusion synovitis and knee pain in older adults.
      . Among those associations, non-weight-bearing pain, measured by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain at night and when lying, suggested to be best correlated with effusion-synovitis
      • Wang X.
      • Jin X.
      • Han W.
      • Cao Y.
      • Halliday A.
      • Blizzard L.
      • et al.
      Cross-sectional and longitudinal associations between knee joint effusion synovitis and knee pain in older adults.
      . A trend of an increased risk of pain with increasing severity of MRI-detected synovitis in hip OA was shown, albeit statistically non-significant
      • Roemer F.W.
      • Hunter D.J.
      • Winterstein A.
      • Li L.
      • Kim Y.J.
      • Cibere J.
      • et al.
      Hip Osteoarthritis MRI Scoring System (HOAMS): reliability and associations with radiographic and clinical findings.
      . Using 0.2T MRI with short tau inversion recovery (STIR) sequence for semi-quantitative assessment of synovitis/effusion, a high prevalence of MRI-detected synovitis/effusion was found in painful hand OA, but little change was observed in the severity of synovitis/effusion between baseline and follow-up
      • Wenham C.Y.
      • Hensor E.M.
      • Grainger A.J.
      • Hodgson R.
      • Balamoody S.
      • Dore C.J.
      • et al.
      A randomized, double-blind, placebo-controlled trial of low-dose oral prednisolone for treating painful hand osteoarthritis.
      . A recent study in patients with hand OA found that ultrasound-detected synovial thickening was associated with pain on palpation of the affected joints
      • Kortekaas M.C.
      • Kwok W.Y.
      • Reijnierse M.
      • Watt I.
      • Huizinga T.W.
      • Kloppenburg M.
      Pain in hand osteoarthritis is associated with inflammation: the value of ultrasound.
      .
      Synovial inflammation was suggested to contribute to knee joint dysfunction using performance-based measures of walking and stair-climbing times
      • Sowers M.
      • Karvonen-Gutierrez C.A.
      • Jacobson J.A.
      • Jiang Y.
      • Yosef M.
      Associations of anatomical measures from MRI with radiographically defined knee osteoarthritis score, pain, and physical functioning.
      . One study of end-stage knee OA patients receiving total knee replacement (TKR) found that synovitis was closely correlated with the functional impairment and disability
      • Liu L.
      • Ishijima M.
      • Futami I.
      • Kaneko H.
      • Kubota M.
      • Kawasaki T.
      • et al.
      Correlation between synovitis detected on enhanced-magnetic resonance imaging and a histological analysis with a patient-oriented outcome measure for Japanese patients with end-stage knee osteoarthritis receiving joint replacement surgery.
      . Despite some disagreements in the literature, the majority of available studies provide compelling evidence that synovial inflammation is a rational target for therapeutic intervention to control symptoms in OA. Future work should help to define specific disease phenotypes or patient populations for whom targeting synovitis may have the greatest benefits.

      Association with structures

      There is evidence to suggest that synovitis and/or effusion detected by MRI or ultrasound were predictors of progression to TKR in prospective studies
      • Conaghan P.G.
      • D'Agostino M.A.
      • Le Bars M.
      • Baron G.
      • Schmidely N.
      • Wakefield R.
      • et al.
      Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large, 3-year, prospective EULAR study.
      • Guermazi A.
      • Kwoh C.K.
      • Hannon M.J.
      • Boudreau B.
      • Hayashi D.
      • Hunter D.J.
      • et al.
      Hoffa-synovitis and effusion-synovitis are associated with knees undergoing total knee replacement: data from the osteoarthritis initiative.
      . However, the causal relationship between synovial inflammation and early osteoarthritic abnormalities is still inconclusive. A study of symptomatic knee OA patients failed to corroborate the associations between longitudinal changes in synovitis and cartilage
      • Hill C.L.
      • Hunter D.J.
      • Niu J.
      • Clancy M.
      • Guermazi A.
      • Genant H.
      • et al.
      Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis.
      . Another study reported that MRI-depicted synovitis was not correlated with radiographic scores, clinical or biologic markers of inflammation in patients with painful hand OA
      • Roux C.H.
      • Foltz V.
      • Maheu E.
      • Baron G.
      • Gandjbakhch F.
      • Lukas C.
      • et al.
      MRI and serum biomarkers correlate with radiographic features in painful hand osteoarthritis.
      . In people with early symptomatic knee OA but no radiographic changes, it was suggested that non-CE-MRI-detected effusion and synovitis were associated with subsequent development of cartilage loss at 30 months
      • Roemer F.W.
      • Guermazi A.
      • Felson D.T.
      • Niu J.
      • Nevitt M.C.
      • Crema M.D.
      • 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.
      . A nested case-control study found that the occurrence of radiographic OA (ROA) was associated with the presence of effusion and/or synovitis at baseline and follow-up, supporting its role in predicting the incidence and development of ROA
      • Atukorala I.
      • Kwoh C.K.
      • Guermazi A.
      • Roemer F.W.
      • Boudreau R.M.
      • Hannon M.J.
      • et al.
      Synovitis in knee osteoarthritis: a precursor of disease?.
      . In an older adults cohort study, effusion-synovitis predicted progression of cartilage defects and subchondral BMLs over 3 years
      • Wang X.
      • Blizzard L.
      • Halliday A.
      • Han W.
      • Jin X.
      • Cicuttini F.
      • et al.
      Association between MRI-detected knee joint regional effusion-synovitis and structural changes in older adults: a cohort study.
      .

      Imaging assessment of synovial abnormalities

      MRI in knee OA

      MRI signs of synovial inflammation include increased synovial thickness/volume, increased signal intensity after intravenous gadolinium injection (enhancement), and increased water content (effusion), alone or in combination
      • Roemer F.W.
      • Guermazi A.
      • Hunter D.J.
      • Niu J.
      • Zhang Y.
      • Englund M.
      • et al.
      The association of meniscal damage with joint effusion in persons without radiographic osteoarthritis: the Framingham and MOST osteoarthritis studies.
      . Non-CE MRI is still the most commonly used modality to assess synovitis in large epidemiological OA studies
      • Baker K.
      • Grainger A.
      • Niu J.
      • Clancy M.
      • Guermazi A.
      • Crema M.
      • et al.
      Relation of synovitis to knee pain using contrast-enhanced MRIs.
      • Rhodes L.A.
      • Grainger A.J.
      • Keenan A.M.
      • Thomas C.
      • Emery P.
      • Conaghan P.G.
      The validation of simple scoring methods for evaluating compartment-specific synovitis detected by MRI in knee osteoarthritis.
      • Guermazi A.
      • Roemer F.W.
      • Hayashi D.
      • Crema M.D.
      • Niu J.
      • Zhang Y.
      • 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.
      • Loeuille D.
      • Chary-Valckenaere I.
      • Champigneulle J.
      • Rat A.C.
      • Toussaint F.
      • Pinzano-Watrin A.
      • et al.
      Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imaging findings with disease severity.
      • Guermazi A.
      • Hayashi D.
      • Roemer F.W.
      • Zhu Y.Y.
      • Niu J.B.
      • Crema M.D.
      • et al.
      Synovitis in knee osteoarthritis assessed by contrast-enhanced magnetic resonance imaging (MRI) is associated with radiographic tibiofemoral osteoarthritis and MRI-detected widespread cartilage damage: the MOST Study.
      , although it has some limitations compared with CE MRI. One distinct disadvantage of non-CE MRI is that it cannot differentiate inflamed synovium from joint effusion which are two highly correlated features. According to a study by Roemer et al., definite synovitis was present in 96.3% knees with an effusion and in 70.0% without an effusion
      • Roemer F.W.
      • Kassim Javaid M.
      • Guermazi A.
      • Thomas M.
      • Kiran A.
      • Keen R.
      • et al.
      Anatomical distribution of synovitis in knee osteoarthritis and its association with joint effusion assessed on non-enhanced and contrast-enhanced MRI.
      . After contrast administration, only inflammatory synovium manifests enhancement, while effusion remains hypo-intense on T1-weighted sequences
      • Roemer F.
      • Javaid M.K.
      • Guermazi A.
      • Thomas M.
      • Kiran A.
      • Keen R.
      • et al.
      Anatomical distribution of synovitis in knee osteoarthritis and its association with joint effusion assessed on non-enhanced and contrast-enhanced MRI.
      . A study compared three methods for evaluating synovitis and joint effusion on MRI with histological changes, and found that only the scoring from CE images correlated with microscopically-proven synovitis
      • Loeuille D.
      • Rat A.C.
      • Goebel J.C.
      • Champigneulle J.
      • Blum A.
      • Netter P.
      • et al.
      Magnetic resonance imaging in osteoarthritis: which method best reflects synovial membrane inflammation? Correlations with clinical, macroscopic and microscopic features.
      .
      There are few studies using dynamic CE MRI, in which early enhancement (i.e., the initial distribution of gadolinium) accurately reflects the inflammatory activity of the joint
      • Ostergaard M.
      • Ejbjerg B.
      Magnetic resonance imaging of the synovium in rheumatoid arthritis.
      • Ostergaard M.
      • Stoltenberg M.
      • Løvgreen-Nielsen P.
      • Volck B.
      • Sonne-Holm S.
      • Lorenzen I.
      Quantification of synovistis by MRI: correlation between dynamic and static gadolinium-enhanced magnetic resonance imaging and microscopic and macroscopic signs of synovial inflammation.
      • Tamai K.
      • Yamato M.
      • Yamaguchi T.
      • Ohno W.
      Dynamic magnetic resonance imaging for the evaluation of synovitis in patients with rheumatoid arthritis.
      . With static CE MRI, the extent of synovial enhancement may be misinterpreted if the assessment is performed on images acquired at a late phase. Because the signal intensity of joint effusion also enhances with time, as gadolinium passes into the joint space by diffusion of fluid from synovial capillaries
      • Ostergaard M.
      • Stoltenberg M.
      • Lovgreen-Nielsen P.
      • Volck B.
      • Jensen C.H.
      • Lorenzen I.
      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.
      . One study showed that dynamic CE MRI with derived pharmacokinetic parameters could provide useful information in differentiating synovitis in hand OA from rheumatoid arthritis (RA)
      • Kirkhus E.
      • Bjørnerud A.
      • Thoen J.
      • Johnston V.
      • Dale K.
      • Smith H.J.
      Contrast-enhanced dynamic magnetic resonance imaging of finger joints in osteoarthritis and rheumatoid arthritis: an analysis based on pharmacokinetic modeling.
      . Another study using a dynamic CE MRI sequence found that quantitative synovial volume was strongly correlated with joint space width (JSW), joint space narrowing (JSN) and BMLs volume in symptomatic knee OA patients
      • Krasnokutsky S.
      • Belitskaya-Levy I.
      • Bencardino J.
      • Samuels J.
      • Attur M.
      • Regatte R.
      • et al.
      Quantitative magnetic resonance imaging evidence of synovial proliferation is associated with radiographic severity of knee osteoarthritis.
      .
      Rhodes et al. demonstrated that semi-quantitative scoring of OA synovitis using CE T1-weighted images was closely related to the quantitative synovial volume
      • Rhodes L.A.
      • Grainger A.J.
      • Keenan A.M.
      • Thomas C.
      • Emery P.
      • Conaghan P.G.
      The validation of simple scoring methods for evaluating compartment-specific synovitis detected by MRI in knee osteoarthritis.
      . This scoring method was subsequently modified and was used in another study which demonstrated that synovitis in the peri-patellar region had a strong correlation with knee pain severity
      • Baker K.
      • Grainger A.
      • Niu J.
      • Clancy M.
      • Guermazi A.
      • Crema M.
      • et al.
      Relation of synovitis to knee pain using contrast-enhanced MRIs.
      . Guermazi et al. assessed synovitis at 11 sites of the entire knee joint in OA patients using CE-MRI
      • Guermazi A.
      • Roemer F.W.
      • Hayashi D.
      • Crema M.D.
      • Niu J.
      • Zhang Y.
      • 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.
      . It was shown that moderate to severe synovitis had a significant association with the maximum WOMAC pain score. Another study has demonstrated an association between meniscal damage of the posterior horns and localised posterior synovitis
      • Roemer F.W.
      • Felson D.T.
      • Yang T.
      • Niu J.
      • Crema M.D.
      • Englund M.
      • 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.
      . Synovitis in knee OA could be assessed using either the semi-quantitative synovial thickness or the quantitative synovial-volume (i.e., whole-knee synovial synovitis) using CE-MRI
      • Crema M.D.
      • Roemer F.W.
      • Li L.
      • Alexander R.C.
      • Chessell I.P.
      • Dudley A.D.
      • et al.
      Comparison between semiquantitative and quantitative methods for the assessment of knee synovitis in osteoarthritis using non-enhanced and gadolinium-enhanced MRI.
      . Compared to semi-quantitative assessment, computer-aided automatic image processing system can quantify the synovial volume which is less observer-dependent but requires longer scanning time
      • Crema M.D.
      • Roemer F.W.
      • Li L.
      • Alexander R.C.
      • Chessell I.P.
      • Dudley A.D.
      • et al.
      Comparison between semiquantitative and quantitative methods for the assessment of knee synovitis in osteoarthritis using non-enhanced and gadolinium-enhanced MRI.
      . Nevertheless, the semi-quantitative method has the advantages of time-saving and adding anatomic information regarding intra-articular synovitis distribution
      • Habib S.
      • Guermazi A.
      • Ozonoff A.
      • Hayashi D.
      • Crema M.D.
      • Roemer F.W.
      MRI-based volumetric assessment of joint effusion in knee osteoarthritis using proton density-weighted fat-suppressed and T1-weighted contrast-enhanced fat-suppressed sequences.
      • Li W.
      • Abram F.
      • Pelletier J.P.
      • Raynauld J.P.
      • Dorais M.
      • d'Anjou M.A.
      • et al.
      Fully automated system for the quantification of human osteoarthritic knee joint effusion volume using magnetic resonance imaging.
      .
      Recent evidence suggested that, when CE MRI is not available, synovitis can be evaluated in combination with effusion, but the inflamed synovium is not distinguishable from joint fluid filling the joint cavity surrounded by synovium because they both show equivalent high signals. Because of this, the phrase “effusion-synovitis” or “synovosis” has been proposed
      • Hunter D.J.
      • Guermazi A.
      • Lo G.H.
      • Grainger A.J.
      • Conaghan P.G.
      • Boudreau R.M.
      • et al.
      Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score).
      (see Fig. 1). Alternatively, synovitis can be assessed indirectly using another surrogate marker, Hoffa's synovitis, which is the hyper-intense signal changes seen within Hoffa's fat pad on non-CE fat-suppressed (FS) proton density (PD) or T2-weighted fast spin echo (FSE) sequences
      • Roemer F.W.
      • Guermazi A.
      • Felson D.T.
      • Niu J.
      • Nevitt M.C.
      • Crema M.D.
      • 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.
      . However, it is noted that the non-specific measures of signal changes in Hoffa's fat pad are not only related to synovitis, but also represent edema, cysts or Hoffa's ganglion
      • Hill C.L.
      • Hunter D.J.
      • Niu J.
      • Clancy M.
      • Guermazi A.
      • Genant H.
      • et al.
      Synovitis detected on magnetic resonance imaging and its relation to pain and cartilage loss in knee osteoarthritis.
      • Roemer F.W.
      • Lynch J.A.
      • Niu J.
      • Zhang Y.
      • Crema M.D.
      • Tolstykh I.
      • et al.
      A comparison of dedicated 1.0 T extremity MRI vs large-bore 1.5 T MRI for semiquantitative whole organ assessment of osteoarthritis: the MOST study.
      .
      Figure thumbnail gr1
      Fig. 1The proton density weighted fat-suppressed MR images show multiple synovial recesses in different subregions of a knee joint. In the central portion of the joint, the synovial fluid can be observed between the patella and femur, extending medially and laterally deep to the patellar retinacula (Fig. 1(A)–(B), arrow). The fluid can also accumulate in the deep part of the central recess, around the anterior cruciate ligament (ACL) and posterior cruciate ligament (PCL) (Fig. 1(B), circle). The synovial fluid can be detected in the suprapatellar pouch which extends superiorly from the upper surface of the patella (Fig. 1(A)–(B), arrow). Posteriorly, synovial fluid extends from lateral and medial sides of the femur and forms recesses above the posterior portions of both condyles (Fig. 1(C), arrow). The sub-popliteal recess is a small pouch that can be seen between the lateral meniscus posteriorly and the popliteus tendon (Fig. 1(D), circle).

      MRI in hip and hand OA

      To date, two semi-quantitative scoring systems are available for MRI evaluation of synovitis in hip OA. One is the Hip OA MRI Score (HOAMS), in which synovitis is one of 14 features of hip OA and CE T1-weighted sequences are used whenever available
      • Roemer F.W.
      • Hunter D.J.
      • Winterstein A.
      • Li L.
      • Kim Y.J.
      • Cibere J.
      • et al.
      Hip Osteoarthritis MRI Scoring System (HOAMS): reliability and associations with radiographic and clinical findings.
      . Synovitis is graded from 0 to 2 at four locations (anterior, posterior, lateral and medial femoral head-neck junction). Another is the Hip Inflammation MRI Scoring System (HIMRISS), in which synovitis is graded from 0 to 2 in combination with effusion, once in 15 slices, giving a maximum score of 30 per hip
      • Lambert R.
      • Maksymowych W.
      • Gracey D.
      Evaluation of bone marrow edema with the hip inflammation MRI scoring system (HIMRISS): is it reliable and do scores correlate with clinical status or response to therapy?.
      . Recently performed validation analyses demonstrated that these two scoring systems are feasible and reliable for the purpose of synovitis assessment in hip OA
      • Maksymowych W.P.
      • Cibere J.
      • Loeuille D.
      • Weber U.
      • Zubler V.
      • Roemer F.W.
      • et al.
      Preliminary validation of 2 magnetic resonance image scoring systems for osteoarthritis of the Hip according to the OMERACT Filter.
      , although these scoring systems have not yet been applied in observational studies or clinical trials and require further validation.
      Synovitis in hand OA can be assessed using an MRI scoring system, the Oslo Hand Osteoarthritis MRI Score (OHOA-MRI)
      • Haugen I.K.
      • Lillegraven S.
      • Slatkowsky-Christensen B.
      • Haavardsholm E.A.
      • Sesseng S.
      • Kvien T.K.
      • et al.
      Hand osteoarthritis and MRI: development and first validation step of the proposed oslo hand osteoarthritis MRI score.
      . Pathological features are assessed at eight locations (distal and proximal interphalangeal joint (PIP)s of the second, third, fourth and fifth fingers) of the dominant hand. Using this system, one study showed that MRI-assessed moderate/severe synovitis was associated with joint tenderness
      • Haugen I.K.
      • Boyesen P.
      • Slatkowsky-Christensen B.
      • Sesseng S.
      • van der Heijde D.
      • Kvien T.K.
      Associations between MRI-defined synovitis, bone marrow lesions and structural features and measures of pain and physical function in hand osteoarthritis.
      . These studies demonstrated that synovitis of hand OA might be a target for therapeutic interventions. Based on OHOA-MRI, the Outcome Measures in Rheumatology (OMERACT) Hand Osteoarthritis MRI Scoring System (HOAMRIS) was iteratively developed. Modifications to the original OHOA-MRI included the exclusion of flexor tenosynovitis and collateral ligament scoring, as well as combining the scoring of distal and proximal parts of distal interphalangeal joint (DIP) and PIP joints and half-grade scoring for some features. The HOAMRIS included semi-quantitative assessment of synovitis in the interphalangeal joints and was shown to be a reliable tool
      • Haugen I.K.
      • Ostergaard M.
      • Eshed I.
      • McQueen F.M.
      • Bird P.
      • Gandjbakhch F.
      • et al.
      Iterative development and reliability of the OMERACT hand osteoarthritis MRI scoring system.
      . However, longitudinal studies are needed to validate these methods for their sensitivity. The MRI scoring systems for evaluation of synovitis and/or effusion in the knee, hip and hand OA are summarised in Table I.
      Table ISummary of semi-quantitative magnetic resonance imaging (MRI) scoring systems for synovial abnormalities in knee, hip and hand OA
      Author (year)AcronymJointEvaluationLocationScoresCE-MRI
      Kaneko (1993)KneeEffusionCentral portion (para-ACL and para-PCL)0–1No
      Suprapatellar pouch0–1No
      Posterior femoral recess0–1No
      Subpopliteal recess0–1No
      Hill (2001)KneeEffusionJoint cavity0–3No
      Peterfy (2004)WORMSKneeEffusion/synovial thickeningJoint cavity0–3No
      Loeullie (2005)MRI synovitis scoreKneeSynovial thickeningMedial and lateral suprapatellar recess0–6Yes
      Trochlear groove0–3Yes
      Medial and lateral femoral gutters0–6Yes
      Kornaat (2005)KOSSKneeEffusionJoint recesses0–2Yes
      Synovial thickeningSynovial joint cavity0–1Yes
      Rhodes (2005)SynovitisPara-patellar recesses0–3Yes
      Hunter (2008)BLOKSKneeEffusionJoint cavity0–3Yes
      SynovitisJoint cavity0–3No
      Pelletier (2008)KneeSynovial thickeningMedial and lateral recesses0–6No
      Medial and lateral suprapatellar bursa0–6No
      Meredith (2009)KneeEffusionJoint cavity0–3No
      SynovitisJoint cavity0–3No
      Baker (2010)KneeSynovial thickeningMedial and lateral para-patellar recesses0–3Yes
      Suprapatellar pouch0–3Yes
      Infrapatellar fat pad0–3Yes
      Medial and lateral posterior femoral condyles0–2Yes
      Baker (2010)WORMSKneeEffusion-synovitisJoint cavity0–3No
      Hunter (2011)MOAKSKneeEffusion-synovitisJoint cavity0–3No
      Hoffa-synovitisHoffa's fat pad0–3No
      Guermazi (2011)KneeSynovial thickeningMedial and lateral para-patellar recesses0–2Yes
      Suprapatellar0–2Yes
      Infrapatellar0–2Yes
      Intercondylar0–2Yes
      Medial and lateral peri-meniscal0–2Yes
      Adjacent to ACL/PCL0–2Yes
      Roemer (2011)HOAMSHipSynovitis

      Effusion
      Lateral, medial, anterior and posterior of the femoral head-neck-junction

      Joint capsular distention
      0–2

      0–2
      Yes
      Lambert (2011)HIMRISSHipEffusion-synovitisCentral, anterior and posterior femoral head and/or neck at the greatest short axis dimension perpendicular to the underlying bone0–2No
      Haugen (2011)OHOA-MRIHandSynovitisDIP and PIP joints0–3Yes
      Haugen (2011)HOAMRISHandSynovitisDIP and PIP joints0–3Yes
      Abbreviations: ACL: anterior cruciate ligament; PCL: posterior cruciate ligament; WORMS: Whole Organ Magnetic Resonance Imaging Score; KOSS: Knee Osteoarthritis Scoring Systems; BLOKS: Boston Leeds Osteoarthritis Knee Score; MOAKS: MRI Osteoarthritis Knee Score; HOAMS: Hip Osteoarthritis MRI Scoring System; HIMRISS: Hip Inflammation MRI Scoring System; OHOA-MRI: Oslo Hand Osteoarthritis MRI score; DIP: distal interphalangeal; PIP: proximal interphalangeal; HOAMRIS: Hand Osteoarthritis Magnetic Resonance Scoring System.

      Ultrasound in knee OA

      Synovitis is readily detected by ultrasound in OA patients and has a similar appearance as that in RA
      • Walther M.
      • Harms H.
      • Krenn V.
      • Radke S.
      • Faehndrich T.P.
      • Gohlke F.
      Correlation of power Doppler sonography with vascularity of the synovial tissue of the knee joint in patients with osteoarthritis and rheumatoid arthritis.
      . Similar to non-CE MRI, ultrasound-detected synovitis in knee OA patients consists of effusion and synovial hypertrophy and is more sensitive than clinical examination
      • Karim Z.
      • Wakefield R.J.
      • Quinn M.
      • Conaghan P.G.
      • Brown A.K.
      • Veale D.J.
      • et al.
      Validation and reproducibility of ultrasonography in the detection of synovitis in the knee: a comparison with arthroscopy and clinical examination.
      . A study reported that power Doppler sonographic assessment of synovitis was well correlated with histological findings of synovial membrane vascularity (β = 0.88–0.89) and allowed further differentiation of the hypertrophic synovium
      • Walther M.
      • Harms H.
      • Krenn V.
      • Radke S.
      • Faehndrich T.P.
      • Gohlke F.
      Correlation of power Doppler sonography with vascularity of the synovial tissue of the knee joint in patients with osteoarthritis and rheumatoid arthritis.
      . A systematic review of ultrasound-detected synovial changes in observational studies reported a significantly higher prevalence of effusion, synovial hypertrophy and Doppler signals in people with knee OA/pain compared to the general population
      • Sarmanova A.
      • Hall M.
      • Moses J.
      • Doherty M.
      • Zhang W.
      Synovial changes detected by ultrasound in people with knee osteoarthritis – a meta-analysis of observational studies.
      . Importantly, this finding suggests that ultrasound-detected synovial changes might correlate with the degree of OA structural change and contribute to disease pathology
      • Hall M.
      • Doherty S.
      • Courtney P.
      • Latief K.
      • Zhang W.
      • Doherty M.
      Synovial pathology detected on ultrasound correlates with the severity of radiographic knee osteoarthritis more than with symptoms.
      , rather than a single biomarker/mechanism that links strongly with pain production. An attempt was recently made to utilise a novel technique of digital synovial vascularisation quantification by using ultrasound with CE for detection of synovitis in people with knee OA. CE-ultrasound showed higher sensitivity (95%) for synovitis detection than CE-MRI (82%), power Doppler ultrasound (64%) or grey-scale ultrasound (58%)
      • Song I.H.
      • Althoff C.E.
      • Hermann K.G.
      • Scheel A.K.
      • Knetsch T.
      • Schoenharting M.
      • et al.
      Knee osteoarthritis. Efficacy of a new method of contrast-enhanced musculoskeletal ultrasonography in detection of synovitis in patients with knee osteoarthritis in comparison with magnetic resonance imaging.
      . Ultrasound was also used to demonstrate short-term synovial responses to intra-articular therapy of the knee
      • Conaghan P.G.
      • D'Agostino M.A.
      • Le Bars M.
      • Baron G.
      • Schmidely N.
      • Wakefield R.
      • et al.
      Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large, 3-year, prospective EULAR study.
      , which supports synovitis as a potential treatment target and a useful outcome measure.

      Ultrasound in hip and hand OA

      In hip OA, Doppler techniques are capable of demonstrating local hyperaemia due to active synovial inflammation
      • Walther M.
      • Harms H.
      • Krenn V.
      • Radke S.
      • Kirschner S.
      • Gohlke F.
      Synovial tissue of the hip at power Doppler US: correlation between vascularity and power Doppler US signal.
      • Schmidt W.A.
      • Volker L.
      • Zacher J.
      • Schlafke M.
      • Ruhnke M.
      • Gromnica-Ihle E.
      Colour Doppler ultrasonography to detect pannus in knee joint synovitis.
      . Ultrasound assessment of the OA hip focused on the presence of effusion or synovitis by assessing the collum-capsule distance (CCD)
      • Bierma-Zeinstra S.M.
      • Bohnen A.M.
      • Verhaar J.A.
      • Prins A.
      • Ginai-Karamat A.Z.
      • Lameris J.S.
      Sonography for hip joint effusion in adults with hip pain.
      . In people with rapidly destructive OA, ultrasound-detected large joint effusions were significantly associated with radiographic findings
      • Birn J.
      • Pruente R.
      • Avram R.
      • Eyler W.
      • Mahan M.
      • van Holsbeeck M.
      Sonographic evaluation of hip joint effusion in osteoarthritis with correlation to radiographic findings.
      . However, it is challenging to exclude hyperaemia of synovial tissue arising from the hip joint due to the depth of effected structures
      • Sudula S.N.
      Imaging the hip joint in osteoarthritis: a place for ultrasound?.
      .
      Several studies on hand OA found that the presence of power Doppler activity and synovitis in finger joints predicted subsequent increased joint damage
      • Keen H.I.
      • Lavie F.
      • Wakefield R.J.
      • D'Agostino M.A.
      • Hammer H.B.
      • Hensor E.
      • et al.
      The development of a preliminary ultrasonographic scoring system for features of hand osteoarthritis.
      • Mancarella L.
      • Magnani M.
      • Addimanda O.
      • Pignotti E.
      • Galletti S.
      • Meliconi R.
      Ultrasound-detected synovitis with power Doppler signal is associated with severe radiographic damage and reduced cartilage thickness in hand osteoarthritis.
      . A preliminary ultrasound-based scoring system for the features of hand OA included evaluation of grey-scale synovitis and power Doppler signal in 15 joints
      • Keen H.I.
      • Hensor E.M.
      • Wakefield R.J.
      • Mease P.J.
      • Bingham 3rd, C.O.
      • Conaghan P.G.
      Ultrasound assessment of response to intra-articular therapy in osteoarthritis of the knee.
      . Overall, the reliability analyses demonstrated moderately good intra- and inter-reader reliabilities without extensive standardisation. This study has indicated that an ultrasound-based outcome measure is feasible for large clinical trials and provided a foundation for further development.

      Other imaging modalities

      Other common imaging modalities such as computed tomography (CT) and positron emission tomography (PET) have also been applied in OA research but have limited clinical application in OA at present. CT without CE is unsuitable for synovitis evaluation because of low soft tissue contrast. Although the role of CE-CT has not been well studied for synovitis assessment in OA, a recent study showed that CE-CT with digital bone masking could be used to demonstrate synovial enhancement in RA patients
      • Polster J.M.
      • Winalski C.S.
      • Sundaram M.
      • Lieber M.L.
      • Schils J.
      • Ilaslan H.
      • et al.
      Rheumatoid arthritis: evaluation with contrast-enhanced CT with digital bone masking.
      . Moderate to high agreement between CE-CT and CE-MRI findings for synovitis and tenosynovitis was demonstrated. Due to a much shorter examination time (average 3.5 min) compared to CE-MRI (average 55 min), all participants preferred CE-CT to CE-MRI
      • Polster J.M.
      • Winalski C.S.
      • Sundaram M.
      • Lieber M.L.
      • Schils J.
      • Ilaslan H.
      • et al.
      Rheumatoid arthritis: evaluation with contrast-enhanced CT with digital bone masking.
      . Additional advantages of CT are its wide-spread availability and cost-efficiency compared to MRI
      • Guermazi A.
      • Roemer F.W.
      • Crema M.D.
      • Englund M.
      • Hayashi D.
      Imaging of non-osteochondral tissues in osteoarthritis.
      . Evaluation of CE-CT in OA patients may be a worthwhile option when access to MRI facilities is limited, or when MRI is contraindicated, but further evaluation is needed to determine its potential role in research and clinical practice.
      PET permits molecular imaging and may have a potential for studying OA synovitis because of the high resolution of commercially available scanners and the possibility of new PET tracers that specifically target molecular pathways associated with synovitis in OA
      • Guermazi A.
      • Roemer F.W.
      • Crema M.D.
      • Englund M.
      • Hayashi D.
      Imaging of non-osteochondral tissues in osteoarthritis.
      . PET uses
      • Wang X.
      • Jin X.
      • Han W.
      • Cao Y.
      • Halliday A.
      • Blizzard L.
      • et al.
      Cross-sectional and longitudinal associations between knee joint effusion synovitis and knee pain in older adults.
      F-fluoro-2-deoxy-d-glucose (FDG) to demonstrates metabolic changes in target tissues and can detect foci of inflammation
      • Schroter G.
      • Schneider-Eicke J.
      • Schwaiger M.
      Assessment of tissue viability with fluorine-18-fluoro-2-deoxyglucose (FDG) and carbon-11-acetate PET imaging.
      . A recent pilot study in knees with medial OA showed a periarticular pattern of increased FDG uptake
      • Nakamura H.
      • Masuko K.
      • Yudoh K.
      • Kato T.
      • Nishioka K.
      • Sugihara T.
      • et al.
      Positron emission tomography with 18F-FDG in osteoarthritic knee.
      . Another study in patients with hand and wrist OA compared the level of FDG uptake with clinical presentations and observed no significant correlation
      • Elzinga E.H.
      • van der Laken C.J.
      • Comans E.F.
      • Lammertsma A.A.
      • Dijkmans B.A.
      • Voskuyl A.E.
      2-Deoxy-2-[F-18]fluoro-D-glucose joint uptake on positron emission tomography images: rheumatoid arthritis versus osteoarthritis.
      . The potential advantages of PET depend on markers targeting specific tissues, of which bone remodelling and turnover in OA have been the primary endpoints to date
      • Kobayashi N.
      • Inaba Y.
      • Tezuka T.
      • Ike H.
      • Kubota S.
      • Kawamura M.
      • et al.
      Evaluation of local bone turnover in painful hip by 18F-fluoride positron emission tomography.
      . At this time, however, the value of PET for the assessment of OA in clinical and research settings has not yet been evaluated.

      Synovial inflammation as a treatment target

      Responsiveness to treatment

      While both ultrasound and MRI may be used to assess inflammation (synovitis and osteitis) and its response to therapy in RA, using these modalities to assess synovitis in OA is still under research. This is largely because there are few studies that have assessed the response to anti-synovial therapies in OA, most of which have failed to show a strong association between a change in synovitis and a change in pain
      • Song I.H.
      • Althoff C.E.
      • Hermann K.G.
      • Scheel A.K.
      • Knetsch T.
      • Schoenharting M.
      • et al.
      Knee osteoarthritis. Efficacy of a new method of contrast-enhanced musculoskeletal ultrasonography in detection of synovitis in patients with knee osteoarthritis in comparison with magnetic resonance imaging.
      • Acebes J.C.
      • Sánchez-Pernaute O.
      • Díaz-Oca A.
      • Herrero-Beaumont G.
      Ultrasonographic assessment of Baker's cysts after intra-articular corticosteroid injection in knee osteoarthritis.
      • Jan M.-H.
      • Chai H.-M.
      • Wang C.-L.
      • Lin Y.-F.
      • Tsai L.-Y.
      Effects of repetitive shortwave diathermy for reducing synovitis in patients with knee osteoarthritis: an ultrasonographic study.
      . Despite one open-label study using methotrexate for knee OA demonstrating a reduction in both ultrasound-detected synovitis and pain
      • Wenham C.Y.
      • Grainger A.J.
      • Hensor E.M.
      • Caperon A.R.
      • Ash Z.R.
      • Conaghan P.G.
      Methotrexate for pain relief in knee osteoarthritis: an open-label study.
      , a proper trial is needed to confirm the finding. It has been suggested that increased power Doppler signal may be associated with increased response to corticosteroid in hand OA
      • Keen H.I.
      • Wakefield R.J.
      • Hensor E.M.
      • Emery P.
      • Conaghan P.G.
      Response of symptoms and synovitis to intra-muscular methylprednisolone in osteoarthritis of the hand: an ultrasonographic study.
      . Another RCT of low-dose oral prednisolone for treating painful hand OA using semi-quantitative assessment of synovitis/effusion reported baseline synovitis/effusion did not predict response to treatment
      • Wenham C.Y.
      • Hensor E.M.
      • Grainger A.J.
      • Hodgson R.
      • Balamoody S.
      • Dore C.J.
      • et al.
      A randomized, double-blind, placebo-controlled trial of low-dose oral prednisolone for treating painful hand osteoarthritis.
      . An exploratory analysis exanimated dynamic CE-MRI-assessed synovial response to intra-articular corticosteroid in knee OA, showing dynamic CE MRI may be more sensitive than a semi-quantitative score at detecting post-therapy synovial change
      • Wenham C.
      • Balamoody S.
      • Grainger A.
      • Hensor E.
      • Draycott S.
      • Hodgson R.
      • et al.
      The responsiveness of novel, dynamic, contrast-enhanced magnetic resonance measures of total knee synovitis after intra-articular corticosteroid for painful osteoarthritis.
      . There was a median 26% reduction in early synovial enhancement rate in participants with good symptomatic response to intra-articular corticosteroid, contrasting with a 23% increase in those who responded poorly
      • Wenham C.
      • Balamoody S.
      • Grainger A.
      • Hensor E.
      • Draycott S.
      • Hodgson R.
      • et al.
      The responsiveness of novel, dynamic, contrast-enhanced magnetic resonance measures of total knee synovitis after intra-articular corticosteroid for painful osteoarthritis.
      . These results may be due to these imaging measures better reflecting true inflammation. However, the lack of predictive value of the current synovitis scoring systems may also reflect their semi-quantitative nature.
      Two recent studies in knee OA patients investigated the responsiveness of CE-MRI quantified synovial measurements after intra-articular steroid injection. One study reported that synovial tissue volume was reduced following steroid therapy in knee OA and its fluctuation correlated with the severity of knee pain
      • Gait A.D.
      • Hodgson R.
      • Parkes M.J.
      • Hutchinson C.E.
      • O'Neill T.W.
      • Maricar N.
      • et al.
      Synovial volume vs synovial measurements from dynamic contrast enhanced MRI as measures of response in osteoarthritis.
      . Another suggested dynamic CE-MRI derived measures of synovial enhancement were more sensitive to the response to treatment and more strongly associated with changes in pain than synovial volume
      • O'Neill T.W.
      • Parkes M.J.
      • Maricar N.
      • Marjanovic E.J.
      • Hodgson R.
      • Gait A.D.
      • et al.
      Synovial tissue volume: a treatment target in knee osteoarthritis (OA).
      . Using non-CE-MRI, quantitative effusion-synovitis volume had better responsiveness to treatment comparing to semi-quantitative scores in an RCT of vitamin D supplementation for treating knee OA patients with low vitamin D level and baseline effusion-synovitis
      • Wang X.
      • Cicuttini F.
      • Jin X.
      • Wluka A.E.
      • Han W.
      • Zhu Z.
      • et al.
      Knee effusion-synovitis volume measurement and effects of vitamin D supplementation in patients with knee osteoarthritis.
      . Yet, there is no optimal synovial assessment in clinical trials and CE-MRI and quantitative synovial measurements are often limited by time and cost when used in large clinical studies. A standardised threshold is also needed to identify whether a change detected by imaging is clinically meaningful.

      New perspectives

      Intra-articular injection or systemic administration of non-steroidal anti-inflammatory drugs (NSAIDs) and steroids, can modulate pain and function during both acute flares and chronic complaints in OA
      • Mathiessen A.
      • Slatkowsky-Christensen B.
      • Kvien T.K.
      • Hammer H.B.
      • Haugen I.K.
      Ultrasound-detected inflammation predicts radiographic progression in hand osteoarthritis after 5 years.
      • Kortekaas M.C.
      • Kwok W.Y.
      • Reijnierse M.
      • Kloppenburg M.
      Inflammatory ultrasound features show independent associations with progression of structural damage after over 2 years of follow-up in patients with hand osteoarthritis.
      . However, the complications caused by drug side-effects and structural deteriorations by repeated injections became problematic during long-term use
      • McAlindon Timothy E.
      • LaValley Michael P.
      • Harvey William F.
      • Price Lori Lyn
      • Driban Jeffrey B.
      • Zhang Ming
      • et al.
      Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial.
      ; thus, routine use of an NSAID or intra-articular steroids is not advisable.
      It has been found that intra-articular injection of HA restores synovial fluid viscoelasticity, decreases pro-inflammatory cytokines by examining synovial fluid aspirations in people with knee OA
      • Vincent H.K.
      • Percival S.S.
      • Conrad B.P.
      • Seay A.N.
      • Montero C.
      • Vincent K.R.
      Hyaluronic acid (HA) viscosupplementation on synovial fluid inflammation in knee osteoarthritis: a pilot Study.
      • Karatay S.
      • Kiziltunc A.
      • Yildirim K.
      • Karanfil R.C.
      • Senel K.
      Effects of different hyaluronic acid products on synovial fluid NO levels in knee osteoarthritis.
      . A synovial biopsy study reported significant decreases in the number of lining cells, macrophages, lymphocytes, mast cells, and increase the number of fibroblasts and the amount of collagen after the intra-articular HA injection
      • Ronchetti I.P.
      • Guerra D.
      • Taparelli F.
      • Boraldi F.
      • Bergamini G.
      • Mori G.
      • et al.
      Morphological analysis of knee synovial membrane biopsies from a randomized controlled clinical study comparing the effects of sodium hyaluronate (Hyalgan®) and methylprednisolone acetate (Depomedrol®) in osteoarthritis.
      . On the contrary, another study found no differences in focal hyperplasia of synovial lining cells, mononuclear inflammation and synovial fluid leukocyte counts between patients treated with and without HA, even if the treatment was proven to be beneficial on walking pain
      • Schumacher H.
      • Paul C.
      • Hitchon C.
      • El-Gabalawy H.
      • Zonay L.
      • Clayburne G.
      • et al.
      Hyaluronate effects on synovium and synovial fluid. A prospective blinded study in patients with osteoarthritis of the knee.
      . Evidence from meta-analyses suggested the clinical effectiveness of intra-articular hyaluronate was at best modest and in some of the meta-analyses, indistinguishable from that of placebo
      • Campbell J.
      • Bellamy N.
      • Gee T.
      Differences between systematic reviews/meta-analyses of hyaluronic acid/hyaluronan/hylan in osteoarthritis of the knee.
      . In many trials of HA, a large placebo effect was observed
      • Zhang W.
      • Robertson J.
      • Jones A.C.
      • Dieppe P.A.
      • Doherty M.
      The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials.
      ; and the potential therapeutic effect of arthrocentesis (with synovial fluid aspiration if needed) may also contribute to the robust response in patients receiving placebo
      • Chevalier X.
      • Jerosch J.
      • Goupille P.
      • van Dijk N.
      • Luyten F.P.
      • Scott D.L.
      • et al.
      Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial.
      .
      It has been suggested that chondroitin may control three aspects of synovial inflammation: cell infiltration and action, biochemical mediators release and angiogenesis
      • Tio L.
      • Orellana C.
      • Perez-Garcia S.
      • Piqueras L.
      • Escudero P.
      • Juarranz Y.
      • et al.
      Effect of chondroitin sulphate on synovitis of knee osteoarthritic patients.
      . After a 10-day treatment of chondroitin, the hyaluronate concentration and intrinsic viscosity were significantly increased, while collagenolytic activity was decreased in the synovial fluid aspirated from people with knee OA
      • Henrotin Y.
      • Lambert C.
      • Richette P.
      Importance of synovitis in osteoarthritis: evidence for the use of glycosaminoglycans against synovial inflammation.
      . Glucosamine and/or chondroitin Arthritis Intervention Trial (GAIT) showed that chondroitin reduced the percentage of knee OA patients with joint swelling and/or effusion by 50% at the end of 24 weeks of treatment
      • Iovu M.
      • Dumais G.
      • du Souich P.
      Anti-inflammatory activity of chondroitin sulfate.
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      .

      Summary

      OA is a highly prevalent disease that causes a formidable burden on individuals and society. Synovial inflammation which occurs at multiple stages of the disease has been considered as an important risk factor in OA disease initiation and progression. Many observational studies demonstrated that synovial inflammation contributes to OA early symptoms and later structural deterioration. Thus, a number of semi-quantitative and quantitative methods have been developed to assess synovial abnormalities in OA using imaging modalities such as MRI and ultrasound. Targeting the inflammatory synovium has great potential to delay or prevent structural alterations and treat symptoms, especially in early OA. So far, very few high-quality clinical trials have used synovial inflammation as an outcome measure and most of them found no clinical benefits. Therefore, well-designed trials of the disease-modifying therapies should consider synovial inflammation as an important treatment target in patients with inflammatory OA phenotypes.

      Author contributions

      All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published.

      Conflict of interest

      Dr. Hunter reports personal fees from Merck Serono, Flexion, Tissuegene, other from DJO Patellofemoral Brace, outside the submitted work.

      Acknowledgments

      We would like to acknowledge Andrew Halliday for providing the MR images. There is no funding source on this work.

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