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Rheumatology Department, Royal North Shore Hospital and Institute of Bone and Joint Research, Kolling Institute, University of Sydney, St. Leonards, New South Wales, Australia
Rheumatology Department, Royal North Shore Hospital and Institute of Bone and Joint Research, Kolling Institute, University of Sydney, St. Leonards, New South Wales, Australia
Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, AustraliaTranslational Research Centre, Academy of Orthopedics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
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.
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
. Evidence also suggests that metabolic dysfunction contributes to forming a potential OA phenotype, sharing a similar aetiology as obesity and diabetes
. 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
. 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)
Comparison between semiquantitative and quantitative methods for the assessment of knee synovitis in osteoarthritis using non-enhanced and gadolinium-enhanced MRI.
. 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
. 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)
. 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
. 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
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
. 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
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
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)
. 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
Bone marrow lesions and joint effusion are strongly and independently associated with weight-bearing pain in knee osteoarthritis: data from the osteoarthritis initiative.
. The independent associations between effusion-synovitis and knee symptoms in early OA highlighted it could trigger symptoms regardless of other structural abnormalities
. 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
. 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
. A recent study in patients with hand OA found that ultrasound-detected synovial thickening was associated with pain on palpation of the affected joints
. 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
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
. 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
. 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
. 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
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
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
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.
Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imaging findings with disease severity.
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
Anatomical distribution of synovitis in knee osteoarthritis and its association with joint effusion assessed on non-enhanced and contrast-enhanced MRI.
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
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
Quantification of synovistis by MRI: correlation between dynamic and static gadolinium-enhanced magnetic resonance imaging and microscopic and macroscopic signs of synovial inflammation.
. 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
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)
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
Rhodes et al. demonstrated that semi-quantitative scoring of OA synovitis using CE T1-weighted images was closely related to the quantitative synovial volume
. 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
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
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
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
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
MRI-based volumetric assessment of joint effusion in knee osteoarthritis using proton density-weighted fat-suppressed and T1-weighted contrast-enhanced fat-suppressed sequences.
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
(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
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
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).
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
. 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
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
. 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
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
. 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)
Acronym
Joint
Evaluation
Location
Scores
CE-MRI
Kaneko (1993)
–
Knee
Effusion
Central portion (para-ACL and para-PCL)
0–1
No
Suprapatellar pouch
0–1
No
Posterior femoral recess
0–1
No
Subpopliteal recess
0–1
No
Hill (2001)
–
Knee
Effusion
Joint cavity
0–3
No
Peterfy (2004)
WORMS
Knee
Effusion/synovial thickening
Joint cavity
0–3
No
Loeullie (2005)
MRI synovitis score
Knee
Synovial thickening
Medial and lateral suprapatellar recess
0–6
Yes
Trochlear groove
0–3
Yes
Medial and lateral femoral gutters
0–6
Yes
Kornaat (2005)
KOSS
Knee
Effusion
Joint recesses
0–2
Yes
Synovial thickening
Synovial joint cavity
0–1
Yes
Rhodes (2005)
–
Synovitis
Para-patellar recesses
0–3
Yes
Hunter (2008)
BLOKS
Knee
Effusion
Joint cavity
0–3
Yes
Synovitis
Joint cavity
0–3
No
Pelletier (2008)
–
Knee
Synovial thickening
Medial and lateral recesses
0–6
No
Medial and lateral suprapatellar bursa
0–6
No
Meredith (2009)
–
Knee
Effusion
Joint cavity
0–3
No
Synovitis
Joint cavity
0–3
No
Baker (2010)
–
Knee
Synovial thickening
Medial and lateral para-patellar recesses
0–3
Yes
Suprapatellar pouch
0–3
Yes
Infrapatellar fat pad
0–3
Yes
Medial and lateral posterior femoral condyles
0–2
Yes
Baker (2010)
WORMS
Knee
Effusion-synovitis
Joint cavity
0–3
No
Hunter (2011)
MOAKS
Knee
Effusion-synovitis
Joint cavity
0–3
No
Hoffa-synovitis
Hoffa's fat pad
0–3
No
Guermazi (2011)
–
Knee
Synovial thickening
Medial and lateral para-patellar recesses
0–2
Yes
Suprapatellar
0–2
Yes
Infrapatellar
0–2
Yes
Intercondylar
0–2
Yes
Medial and lateral peri-meniscal
0–2
Yes
Adjacent to ACL/PCL
0–2
Yes
Roemer (2011)
HOAMS
Hip
Synovitis Effusion
Lateral, medial, anterior and posterior of the femoral head-neck-junction Joint capsular distention
0–2 0–2
Yes
Lambert (2011)
HIMRISS
Hip
Effusion-synovitis
Central, anterior and posterior femoral head and/or neck at the greatest short axis dimension perpendicular to the underlying bone
0–2
No
Haugen (2011)
OHOA-MRI
Hand
Synovitis
DIP and PIP joints
0–3
Yes
Haugen (2011)
HOAMRIS
Hand
Synovitis
DIP and PIP joints
0–3
Yes
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.
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
. 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
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
. Importantly, this finding suggests that ultrasound-detected synovial changes might correlate with the degree of OA structural change and contribute to disease pathology
, 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%)
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.
Several studies on hand OA found that the presence of power Doppler activity and synovitis in finger joints predicted subsequent increased joint damage
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
. 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
. 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
. 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
. Another study in patients with hand and wrist OA compared the level of FDG uptake with clinical presentations and observed no significant correlation
. 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
. 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
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.
, 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
. 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
. 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
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
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
. 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
. 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
. 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
Inflammatory ultrasound features show independent associations with progression of structural damage after over 2 years of follow-up in patients with hand osteoarthritis.
; 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
. 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
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
. 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
; and the potential therapeutic effect of arthrocentesis (with synovial fluid aspiration if needed) may also contribute to the robust response in patients receiving placebo
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
. 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
. 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
. A more recent RCT showed that chondroitin sulfate comparing to acetaminophen prevented synovitis onset or progression in people with knee OA and synovial inflammation
. Similar to HA, meta-analyses of RCTs suggested there was no good evidence to support the use of chondroitin and/or glucosamine for hip or knee OA and an absence of evidence to support specific treatment consideration for OA subgroup according to baseline pain severity, structural abnormalities or presence of inflammation
Subgroup analyses of the effectiveness of oral glucosamine for knee and hip osteoarthritis: a systematic review and individual patient data meta-analysis from the OA trial bank.
Designed to interfere with specific targets, the novel therapies include anti-fibrotic agents, biologic agents such as anti-TNF monoclonal antibodies, anti-nerve growth factor (NGF) antibodies and anti-proteases. RCTs of adalimumab, the first bioengineered fully humanised anti-TNF monoclonal antibody, have reported no effects in hand OA
Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-controlled trial.
, although a subgroup analysis reported less erosive evolution on the radiographic image in the treatment group than placebo in patients with erosive hand OA and baseline synovitis
Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification.
Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial.
, did not show statistically significant benefits on symptoms in human clinical trials. Using both CE MRI and CE ultrasound to assess synovial inflammation, an RCT of a bradykinin receptor-2 antagonist, icatibant, showed an analgesic effect in symptomatic knee OA patients, especially for pain during activity in the high-dose group
. Another analysis on structural effects of sprifermin, a recombinant human fibroblast growth factor 18, found less worsening of cartilage damage and BMLs although no significant effects were seen in Hoffa's synovitis, effusion-synovitis, menisci and osteophytes
Structural effects of sprifermin in knee osteoarthritis: a post-hoc analysis on cartilage and non-cartilaginous tissue alterations in a randomized controlled trial.
. Although current evidence in the investigation of anti-synovitis interventions in OA is limited, there is an upward trend to use synovial inflammation as an outcome measure in RCTs in the near future
Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial.
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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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.
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.
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.
Macroscopic and microscopic features of synovial membrane inflammation in the osteoarthritic knee: correlating magnetic resonance imaging findings with disease severity.
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.
Anatomical distribution of synovitis in knee osteoarthritis and its association with joint effusion assessed on non-enhanced and contrast-enhanced MRI.
Anatomical distribution of synovitis in knee osteoarthritis and its association with joint effusion assessed on non-enhanced and contrast-enhanced MRI.
Magnetic resonance imaging in osteoarthritis: which method best reflects synovial membrane inflammation? Correlations with clinical, macroscopic and microscopic features.
Quantification of synovistis by MRI: correlation between dynamic and static gadolinium-enhanced magnetic resonance imaging and microscopic and macroscopic signs of synovial inflammation.
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.
Contrast-enhanced dynamic magnetic resonance imaging of finger joints in osteoarthritis and rheumatoid arthritis: an analysis based on pharmacokinetic modeling.
The association between meniscal damage of the posterior horns and localized posterior synovitis detected on T1-weighted contrast-enhanced MRI—the MOST study.
MRI-based volumetric assessment of joint effusion in knee osteoarthritis using proton density-weighted fat-suppressed and T1-weighted contrast-enhanced fat-suppressed sequences.
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?.
Associations between MRI-defined synovitis, bone marrow lesions and structural features and measures of pain and physical function in hand osteoarthritis.
Correlation of power Doppler sonography with vascularity of the synovial tissue of the knee joint in patients with osteoarthritis and rheumatoid arthritis.
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-detected synovitis with power Doppler signal is associated with severe radiographic damage and reduced cartilage thickness in hand osteoarthritis.
The responsiveness of novel, dynamic, contrast-enhanced magnetic resonance measures of total knee synovitis after intra-articular corticosteroid for painful osteoarthritis.
Inflammatory ultrasound features show independent associations with progression of structural damage after over 2 years of follow-up in patients with hand osteoarthritis.
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.
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.
Subgroup analyses of the effectiveness of oral glucosamine for knee and hip osteoarthritis: a systematic review and individual patient data meta-analysis from the OA trial bank.
Adalimumab in patients with hand osteoarthritis refractory to analgesics and NSAIDs: a randomised, multicentre, double-blind, placebo-controlled trial.
Tumour necrosis factor blockade for the treatment of erosive osteoarthritis of the interphalangeal finger joints: a double blind, randomised trial on structure modification.
Autologous interleukin-1 receptor antagonist improves function and symptoms in osteoarthritis when compared to placebo in a prospective randomized controlled trial.
Structural effects of sprifermin in knee osteoarthritis: a post-hoc analysis on cartilage and non-cartilaginous tissue alterations in a randomized controlled trial.
Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial.
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