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The effects of intra-articular glucocorticoids and exercise on pain and synovitis assessed on static and dynamic magnetic resonance imaging in knee osteoarthritis: exploratory outcomes from a randomized controlled trial

Open ArchivePublished:October 13, 2016DOI:https://doi.org/10.1016/j.joca.2016.10.009

      Summary

      Objective

      The aims of the present knee osteoarthritis (KOA)-study were to: (1) describe and compare the changes in magnetic resonance imaging (MRI)-measures of synovitis following an exercise program preceded by an intra-articular injection of either corticosteroid or isotonic saline and (2) investigate if any of the changes in patient reported outcome measures (PROMs) were associated with changes in MRI-measures of synovitis.

      Design

      We performed a randomized, double-blinded, placebo-controlled clinical trial evaluating the effects of intra-articular corticosteroid vs placebo injections given before exercise therapy in KOA-patients. PROMs were assessed using the KOOS (knee injury and osteoarthritis outcome score). Synovitis was assessed on conventional non-contrast-enhanced, conventional contrast-enhanced (CE) and dynamic contrast-enhanced (DCE) MRI. PROMs and MRIs were obtained prior to the intra-articular injection, after termination of the exercise program (week 14—primary time point) and week 26.

      Results

      Of 100 randomized participants (50 in each allocation group), 91 had complete MRI-data at baseline (63% female, mean age: 62 years, median Kellgren–Lawrence-grade: 3). There were no statistically significant differences between the two interventions in regards of changes in MRI-measures of synovitis at any time-point. At week 14, we found no statistical significant MRI-explanatory variables of either of the PROMs.

      Conclusions

      The present study does not justify the use of intra-articular corticosteroids over intra-articular saline when combined with an exercise program for reduction of synovitis in KOA. The improvement in pain and function following the intervention with intra-articular corticosteroids/saline and exercise could not be explained by a decrease in synovitis on MRI indicating other pain causing/relieving mechanisms in KOA.

      Keywords

      Introduction

      Synovitis is the hallmark of intra-articular inflammation and a common finding in all stages of knee osteoarthritis (OA)
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      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.
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      Imaging of non-osteochondral tissues in osteoarthritis.
      . It is generally accepted that synovitis is associated with pain in knee OA
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      Structural correlates of pain in joints with osteoarthritis.
      . Synovitis has also been associated with structural disease severity and cartilage loss in both established knee OA
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      • Hirko K.
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      • Li L.
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      Systematic review of the concurrent and predictive validity of MRI biomarkers in OA.
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      • Crema M.D.
      • Marra M.D.
      • et al.
      Tibiofemoral joint osteoarthritis: risk factors for MR-depicted fast cartilage loss over a 30-month period in the multicenter osteoarthritis study.
      , in persons at risk of knee OA
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      Synovitis in knee osteoarthritis: a precursor of disease?.
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      • Roemer F.
      • et al.
      Synovitis and the risk of knee osteoarthritis: the MOST Study.
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      • 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.
      as well as a risk factor for total knee arthroplasty (TKA)
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      • et al.
      Synovitis and the risk of knee osteoarthritis: the MOST Study.
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      • Wang Z.
      • et al.
      Can structural joint damage measured with MR imaging be used to predict knee replacement in the following year?.
      . As a consequence hereof, synovitis is increasingly being addressed as a treatment target in both pre-knee OA and established knee OA.
      Synovitis can be assessed on magnetic resonance imaging (MRI), optimally on contrast-enhanced (CE)-MRI, as only this allows the discrimination of the synovium from a joint effusion
      • 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.
      • Hayashi D.
      • Roemer F.W.
      • Guermazi A.
      Imaging for osteoarthritis.
      . When performing CE-MRI, a dynamic contrast-enhanced (DCE)-MRI sequence can be added.
      In DCE-MRI, imaging is not only performed before and after but also during the intravenous (IV) injection of gadolinium (Gd). DCE-MRI data are typically analyzed using either a heuristic or pharmacokinetic approach. Heuristic analyses are based on the changes in signal intensity over time following Gd-injection (so-called time-intensity-curves, TICs). Pharmacokinetic analysis relies on converting TICs to concentration-time-curves (CTCs), i.e., changes in Gd-concentration over time; by fitting data from the CTCs with pharmacokinetic models, e.g., the extended Tofts model, pharmacokinetic parameters such as Ktrans, a measure of capillary permeability, can be extracted.
      As the distribution of Gd depends on the perfusion, DCE-MRI parameters can be used as surrogate markers of perfusion and DCE-MRI parameters from the synovium
      • Riis R.G.
      • Gudbergsen H.
      • Henriksen M.
      • Ballegaard C.
      • Bandak E.
      • Röttger D.
      • et al.
      Synovitis assessed on static and dynamic contrast-enhanced magnetic resonance imaging and its association with pain in knee osteoarthritis: a cross-sectional study.
      and Hoffa's fat pad
      • Ballegaard C.
      • Riis R.G.
      • Bliddal H.
      • Christensen R.
      • Henriksen M.
      • Bartels E.M.
      • et al.
      Knee pain and inflammation in the infrapatellar fat pad estimated by conventional and dynamic contrast-enhanced magnetic resonance imaging in obese patients with osteoarthritis: a cross-sectional study.
      have recently been shown to correlate with pain and function in knee OA. In addition, recent studies have shown that DCE-MRI variables are more sensitive to changes following treatment with intra-articular corticosteroid compared to measures of the synovial volume
      • 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.
      and a semi-quantitative CE-MRI score
      • Wenham C.Y.
      • Balamoody S.
      • Grainger A.J.
      • Hensor E.M.
      • 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.
      which also seems to be the case in rheumatoid arthritis (RA)
      • Boesen M.
      • Kubassova O.
      • Cimmino M.A.
      • Ostergaard M.
      • Taylor P.
      • Danneskiold-Samsoe B.
      • et al.
      Dynamic contrast enhanced MRI can monitor the very early inflammatory treatment response upon intra-articular steroid injection in the knee joint: a case report with review of the literature.
      .
      Intra-articular corticosteroids have been used in knee OA for several decades. The therapeutic response is probably due to their anti-inflammatory effect and intra-articular corticosteroids as well as exercise are widely recommended in the non-surgical management of knee OA
      • American Academy of Orthopaedic Surgeons
      Treatment of Osteoarthritis of the Knee – Evidence-based Guidelines.
      • Fernandes L.
      • Hagen K.B.
      • Bijlsma J.W.
      • Andreassen O.
      • Christensen P.
      • Conaghan P.G.
      • et al.
      EULAR recommendations for the non-pharmacological core management of hip and knee osteoarthritis.
      • Hochberg M.C.
      • Altman R.D.
      • April K.T.
      • Benkhalti M.
      • Guyatt G.
      • McGowan J.
      • et al.
      American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee.
      • McAlindon T.E.
      • Bannuru R.R.
      • Sullivan M.C.
      • Arden N.K.
      • Berenbaum F.
      • Bierma-Zeinstra S.M.
      • et al.
      OARSI guidelines for the non-surgical management of knee osteoarthritis.
      • Nelson A.E.
      • Allen K.D.
      • Golightly Y.M.
      • Goode A.P.
      • Jordan J.M.
      A systematic review of recommendations and guidelines for the management of osteoarthritis: the chronic osteoarthritis management initiative of the U.S. bone and joint initiative.
      .
      Our study is part of a randomized, double-blinded, placebo-controlled, clinical knee OA-trial in which no benefit of intra-articular corticosteroids compared to intra-articular saline administered prior to an exercise program could be detected, neither in regards of clinical outcomes
      • Henriksen M.
      • Christensen R.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Ellegaard K.
      • et al.
      Evaluation of the benefit of corticosteroid injection before exercise therapy in patients with osteoarthritis of the knee: a randomized clinical trial.
      • Soriano-Maldonado A.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Ellegaard K.
      • Bliddal H.
      • et al.
      Intra-articular corticosteroids in addition to exercise for reducing pain sensitivity in knee osteoarthritis: exploratory outcome from a randomized controlled trial.
      , nor in regards of ultrasonography-assessed measures of knee joint inflammation
      • Henricsdotter C.
      • Ellegaard K.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Bartels E.M.
      • et al.
      Changes in ultrasound assessed markers of inflammation following intra-articular steroid injection combined with exercise in knee osteoarthritis: exploratory outcome from a randomized trial.
      . It however remains unknown what the effects on MRI-measures of synovitis are. As synovitis seems to play a role in the development and progression of knee OA, interventions that reduce synovitis in the long term could have important clinical implications for the management of persons with or at risk of knee OA.
      The aims of our study were to: (1) describe and compare the changes in MRI-measures of synovitis following an exercise program preceded by an intra-articular injection of either corticosteroid or isotonic saline, and (2) investigate if any of the changes in patient reported outcome measures (PROMs) were associated with changes in MRI-measures of synovitis. We hypothesized that (1) the combination of steroid and exercise was more effective in reducing synovitis assessed on MRI compared to isotonic saline and exercise, and (2) the improvement in PROMs was paralleled by a reduction in MRI-measures of synovitis.

      Methods

      The main clinical trial was a participant-, care provider-, outcome assessor blinded, two-arm, parallel-group, randomized and placebo-controlled trial, running over 26 weeks from October 2012 to April 2014 with patient-reported pain as primary outcome
      • Henriksen M.
      • Christensen R.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Ellegaard K.
      • et al.
      Evaluation of the benefit of corticosteroid injection before exercise therapy in patients with osteoarthritis of the knee: a randomized clinical trial.
      . The results of the primary and key secondary outcomes can be found elsewhere
      • Henriksen M.
      • Christensen R.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Ellegaard K.
      • et al.
      Evaluation of the benefit of corticosteroid injection before exercise therapy in patients with osteoarthritis of the knee: a randomized clinical trial.
      • Soriano-Maldonado A.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Ellegaard K.
      • Bliddal H.
      • et al.
      Intra-articular corticosteroids in addition to exercise for reducing pain sensitivity in knee osteoarthritis: exploratory outcome from a randomized controlled trial.
      • Henricsdotter C.
      • Ellegaard K.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Bartels E.M.
      • et al.
      Changes in ultrasound assessed markers of inflammation following intra-articular steroid injection combined with exercise in knee osteoarthritis: exploratory outcome from a randomized trial.
      . The protocol was registered with the EU clinical trials register (Eudra-CT number: 2012-002607-18) and was approved by the Danish Health and Medicines Authority and the Regional Health Research Ethics Committee. The trial was conducted in accordance with the Declaration of Helsinki and ICH Good Clinical Practice.

      Setting and eligibility criteria

      Participants were recruited from the OA outpatient clinic, Copenhagen University Hospital, Bispebjerg-Frederiksberg, Denmark. Inclusion criteria included: age ≥ 40 years, radiographically verified diagnosis of tibiofemoral OA (American College of Rheumatology-criteria), clinical signs of localized knee inflammation, knee pain during walking (> 4 on a 0–10 point scale), and a body mass index (BMI) ≤ 35 kg/m2. Exclusion criteria included: corticosteroid injections or participation in exercise therapy within 3 months, current/recent (within 4 weeks) use of oral corticosteroids, contraindications to corticosteroid injections, conditions precluding participation in exercise, inflammatory arthritis, history of knee arthroplasty or osteotomy, generalized pain syndromes (e.g., fibromyalgia) or local nerve root compression syndromes. Only participants without contraindications underwent MRI. The contrast agent was only administered to participants with an estimated glomerular filtration rate ≥ 60 ml/min/1.73 m2. All participants gave their oral and written informed consent.

      Procedures

      The participants chose the most symptomatic knee as target knee for injection and all subsequent assessments. Upon complete baseline assessments, participants were randomized and the injection was performed. The exercise program commenced two weeks after the baseline assessments and lasted for 12 weeks. The exercise program was identical in both allocation groups.

      Randomization, treatment allocation, and blinding

      Participants were randomized equally (1:1) to an intra-articular injection of either corticosteroid or placebo. The pre-specified allocation list was concealed in a password-protected computer file. Individual allocations were held in sealed, opaque, and consecutively numbered envelopes. Syringes were prepared by an un-blinded study nurse in the absence of participants and blinded study staff. Details about the randomization, allocations and blinding can be found elsewhere
      • Henriksen M.
      • Christensen R.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Ellegaard K.
      • et al.
      Evaluation of the benefit of corticosteroid injection before exercise therapy in patients with osteoarthritis of the knee: a randomized clinical trial.
      .

      Sample size

      The hosting study was powered for a comparison in the pain subscale of the KOOS (knee injury and osteoarthritis outcome score) between the two allocation groups and included 100 individuals
      • Henriksen M.
      • Christensen R.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Ellegaard K.
      • et al.
      Evaluation of the benefit of corticosteroid injection before exercise therapy in patients with osteoarthritis of the knee: a randomized clinical trial.
      .

      Interventions

      Intra-articular injections were performed by an experienced musculoskeletal (MSK) sonographer (KE) under ultrasound (US) guidance ensuring correct bolus deposition in the joint cavity. If present, excess joint fluid was aspirated prior to injection. Participants in the corticosteroid group received an intra-articular injection of 1 ml methylprednisolone (40 mg/ml) dissolved in 4 ml lidocaine (10 mg/ml); participants in the placebo group received an injection of 1 ml isotonic saline with 4 ml lidocaine (10 mg/ml).
      The exercise intervention consisted of a facility-based, functional and individualized exercise program supervised by a trained physiotherapist (CB) three times weekly for 12 weeks. Details about the exercise program can be found elsewhere
      • Henriksen M.
      • Christensen R.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Ellegaard K.
      • et al.
      Evaluation of the benefit of corticosteroid injection before exercise therapy in patients with osteoarthritis of the knee: a randomized clinical trial.
      • Henriksen M.
      • Klokker L.
      • Graven-Nielsen T.
      • Bartholdy C.
      • Schjodt J.T.
      • Bandak E.
      • et al.
      Association of exercise therapy and reduction of pain sensitivity in patients with knee osteoarthritis: a randomized controlled trial.
      .

      MRI

      MRI of the target knee was performed on a 3 Tesla Siemens Verio® system using a dedicated 15 channel send/receive knee coil. MRI was only acquired in participants without contraindications to MRI with the following protocol: gradient echo (GRE) scout (slice thickness (ST) 8 mm, field of view (FOV) 400 × 400 mm, TE 3.69 ms, TR 7.8 ms); coronal/axial T1-weighted (T1w) turbo spin echo (TSE) (ST 3.5 mm, 150 × 150 mm, matrix resolution 0.6 × 0.5 × 3.5 mm, TE 17 ms, TR 790 ms); coronal/sagittal short tau inversion recovery (STIR) (ST 3 mm, 160 × 160 mm, 0.7 × 0.6 × 3 mm, TI 220 ms, TE 34 ms, TR 4350 ms); sagittal 3D proton density weighted (PDw) fat-suppressed (fs) TSE SPACE (ST 0.6 mm, 160 × 160 mm, 0.6 × 0.5 × 0.6 mm, TE 44 ms, TR 1000 ms); sagittal GRE 3D T1w VIBE (ST 0.6 mm, 160 × 160 mm, 0.6 × 0.6 × 0.6 mm, flip angle (FA) 10°, TE 5.39 ms, TR 11.6 ms). Just prior to and simultaneously with the IV injection of 0.2 ml/kg Gadoteridol (Prohance®, Bracco Diagnostics Inc., Italy) using a power injector, a sequential sagittal custom made DCE-MRI GRE T1w VIBE sequence was performed using 4 mm slices every 9 s with 30 repetitions (TE 1.86, TR 5.51, FA 15°, FOV 160 × 160 mm, matrix resolution 256 × 256). Following this, the static 3D GRE T1w VIBE sequence was repeated. Total imaging time was 30–40 min.

      MRI-analyses

      Static, conventional MRI

      On static, non-CE-MRI, synovitis was assessed according to the MOAKS (MRI in OA Knee Score)
      • 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).
      using the 3D PDw sequence: the two subscales, i.e., Effusion-Synovitis and Hoffa-Synovitis, each scored 0–3, were summed into one single MOAKS-Synovitis score (0–6).
      On static CE-MRI, synovitis was assessed according to the whole-knee synovitis score as proposed by Guermazi et al.
      • 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.
      , using the sagittal and reconstructed axial post-Gd GRE 3D T1w VIBE. Furthermore, effusion was assessed (0–3) on the same sequence according to the BLOKS (Boston–Leeds OA Knee Score)
      • Hunter D.J.
      • Lo G.H.
      • Gale D.
      • Grainger A.J.
      • Guermazi A.
      • Conaghan P.G.
      The reliability of a new scoring system for knee osteoarthritis MRI and the validity of bone marrow lesion assessment: BLOKS (Boston Leeds Osteoarthritis Knee Score).
      . As effusion can only be differentiated from synovitis on CE-MRI, the BLOKS-Effusion score reflects only the joint effusion itself, whereas the MOAKS Effusion-Synovitis score (on non-CE-MRI) represents the combination of effusion and synovitis. Details about the static MRI assessments can be found in Supplemental file 1.

      DCE-MRI

      DCE-MRI analyses were performed by a resident in radiology (RR) with no clinical involvement in the trial and with 4 years of experience in DCE-MRI and semi-quantitative MRI analysis of knee OA (MOAKS, BLOKS). Prior to the analyses, all MRIs were assessed for eligibility (e.g., assessing motion artifacts) and a training session with 10 MRIs was performed with a MSK radiologist (MB) with more than 12 years of experience in knee OA MRI and DCE-MRI analyses.
      By subtracting the first repetition of the DCE-MRI sequence from the last repetition using OsiriX v. 7.0, we created a sequence consisting of only enhancing voxels which allowed us to draw regions of interest (ROIs) covering the entire enhancing synovium (Fig. 1). These ROIs were subsequently automatically transposed to the motion-corrected DCE-MRI sequence and collapsed into one single volume of interest (VOI) from which heuristic and pharmacokinetic parameters were calculated and extracted. Dynamika v. 4.1 (www.imageanalysis.org.uk) was used for all DCE-MRI analyses.
      Fig. 1
      Fig. 1Synovitis on DCE-MRI. AC: creation of the “Gd-enhancement-sequence” (C) by subtracting the first repetition of the DCE-MRI sequence (A) from the last repetition (B). ROIs are drawn around the enhancing synovium on the Gd-enhancement-sequence and automatically transposed to the motion corrected DCE-MRI sequence. The dark areas represent effusion and were included in the ROIs as this does not influence any of the DCE-MRI parameters/variable (effusion is non-enhancing and thus registered as none-enhancing voxels in Dynamika and no DCE-MRI parameters are calculated for such voxels). The inclusion of effusion in DCE-MRI analyses of synovitis has been used before
      • Riis R.G.
      • Gudbergsen H.
      • Henriksen M.
      • Ballegaard C.
      • Bandak E.
      • Röttger D.
      • et al.
      Synovitis assessed on static and dynamic contrast-enhanced magnetic resonance imaging and its association with pain in knee osteoarthritis: a cross-sectional study.
      . DE: parametric maps. Brighter colors indicate higher values. (D): IRE-map; (E): Ktrans-map.

      Heuristic DCE-MRI analyses

      Tissues with high perfusion are characterized by a steep upslope/high IRE and rapid washout on the TICs. Tissues with lower perfusion show a slower increase in Gd-uptake and will eventually not reach a plateau or washout phase. Based on the shape of the TIC, Dynamika automatically assigns every voxel to one of four perfusion patterns: no enhancement (no color), persistent (voxels that do not reach a plateau phase—blue), plateau (voxels that reach a plateau but not a washout phase—green) and washout (voxels that reach a washout phase—red). As a voxel represents a volume, we converted the number of the highest perfused voxels (voxels with plateau or washout patterns) in the VOI into a volume (ml) of synovitis (Nvoxel). From the TICs of the ROIs, we also used the mean initial rate of enhancement (IRE, the upslope on the TIC) and mean maximum enhancement (ME). We multiplied Nvoxel by the IRE and ME, creating two composite variables, IRE × Nvoxel and ME × Nvoxel, reflecting both the volume and degree of perfusion, and additionally multiplied the IRE by the ME. Nvoxel, IRE × Nvoxel, ME × Nvoxel and IRE × ME are heuristic DCE-MRI variables that have been used previously in both RA
      • Axelsen M.B.
      • Stoltenberg M.
      • Poggenborg R.P.
      • Kubassova O.
      • Boesen M.
      • Bliddal H.
      • et al.
      Dynamic gadolinium-enhanced magnetic resonance imaging allows accurate assessment of the synovial inflammatory activity in rheumatoid arthritis knee joints: a comparison with synovial histology.
      • Axelsen M.
      • Poggenborg R.
      • Stoltenberg M.
      • Kubassova O.
      • Boesen M.
      • Horslev-Petersen K.
      • et al.
      Reliability and responsiveness of dynamic contrast-enhanced magnetic resonance imaging in rheumatoid arthritis.
      and knee OA-studies
      • Riis R.G.
      • Gudbergsen H.
      • Henriksen M.
      • Ballegaard C.
      • Bandak E.
      • Röttger D.
      • et al.
      Synovitis assessed on static and dynamic contrast-enhanced magnetic resonance imaging and its association with pain in knee osteoarthritis: a cross-sectional study.
      • Ballegaard C.
      • Riis R.G.
      • Bliddal H.
      • Christensen R.
      • Henriksen M.
      • Bartels E.M.
      • et al.
      Knee pain and inflammation in the infrapatellar fat pad estimated by conventional and dynamic contrast-enhanced magnetic resonance imaging in obese patients with osteoarthritis: a cross-sectional study.
      • Bandak E.
      • Boesen M.
      • Bliddal H.
      • Riis R.G.
      • Gudbergsen H.
      • Henriksen M.
      Associations between muscle perfusion and symptoms in knee osteoarthritis: a cross sectional study.
      .

      Pharmacokinetic DCE-MRI analyses

      The pharmacokinetic analyses were performed by first manually choosing an area within the popliteal artery with a clear arterial TIC (steep upslope and rapid washout) for the arterial input function (AIF). Signal intensities from the TICs were then converted into CTCs and data from these were subsequently fitted the extended Tofts model. As the temporal resolution was relatively high (nine seconds), we used the raw data of the individual arterial TICs and AIFs; this method has been used previously
      • Riis R.G.
      • Gudbergsen H.
      • Henriksen M.
      • Ballegaard C.
      • Bandak E.
      • Röttger D.
      • et al.
      Synovitis assessed on static and dynamic contrast-enhanced magnetic resonance imaging and its association with pain in knee osteoarthritis: a cross-sectional study.
      • Rijpkema M.
      • Kaanders J.H.
      • Joosten F.B.
      • van der Kogel A.J.
      • Heerschap A.
      Method for quantitative mapping of dynamic MRI contrast agent uptake in human tumors.
      . Non-linear fitting of the data was performed on a voxel-by-voxel basis using the Levenberg–Marquardt algorithm and the point of interest for the AIF was in all cases manually selected by the same reader (RR).
      From the extended Tofts model, we used Ktrans, the volume transfer coefficient for passage of Gd from blood vessels to the extracellular space over time (min−1) and thus a measure of capillary permeability, and Ve, the proportion (between 0 and 1) of extravascular extracellular space in the tissue (a measure of interstitial edema). In addition we used iAUGC60, the initial area (first 60 s) under the concentration-time-curve, a measure of Gd-accumulation—and thus perfusion—in the synovium. The pharmacokinetic analyses are described in details in Supplemental file 1.
      Intra-reader reliability analyses, based on 10 MRI-datasets with a minimum of four weeks between first and second reading, revealed intra-class correlation coefficients (ICCs) between 0.76 and 0.94 for the static MRI-variables, 0.68–0.95 for the pharmacokinetic DCE-MRI parameters and 0.97–1.00 for the heuristic DCE-MRI variables. The ICCs and results from the correlation and sensitivity analyses are shown in details in Supplemental file 2.

      PROMs

      We used the five domains (pain, symptoms, function in daily living (ADL), function in sport/recreation (Sport/Rec), knee-related quality of life (QOL)) of the KOOS (0: extreme pain/symptoms; 100: no pain/symptoms)
      • Roos E.M.
      • Toksvig-Larsen S.
      Knee injury and Osteoarthritis Outcome Score (KOOS) – validation and comparison to the WOMAC in total knee replacement.
      .

      Outcome measures

      Outcome measures were measured at baseline, week 14 (primary time point) and week 26 (follow-up). The primary outcome measure of the hosting study was the change in KOOS-Pain from baseline to week 14
      • Henriksen M.
      • Christensen R.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Ellegaard K.
      • et al.
      Evaluation of the benefit of corticosteroid injection before exercise therapy in patients with osteoarthritis of the knee: a randomized clinical trial.
      . In this exploratory MRI-study, static non-contrast-enhanced, static CE, and DCE-MRI assessments of synovitis were included.

      Major outcome measure

      The major outcome in our MRI-study was the heuristic DCE-MRI variable ME × Nvoxel, a composite score reflecting both the Nvoxel and degree of perfusion in the synovium (ME).

      Minor outcome measures

      The remaining MRI-variables and PROMs constituted the minor outcome measures. All outcome measures are summarized and explained in Table I. In addition, the following patient characteristics were assessed: age, gender, BMI, CRP (C-reactive protein) and Kellgren–Lawrence grade of the target knee.
      Table IOutcome measures
      PROMsKOOS-PainPain domain of the knee injury and OA outcome score (KOOS). 0 indicates extreme pain, 100 indicates no pain.
      KOOS-SymptomsKnee related symptoms domain of the knee injury and OA outcome score (KOOS). 0 indicates extreme symptoms, 100 indicates no symptoms.
      KOOS-ADLFunction in daily living domain of the knee injury and OA outcome score (KOOS). 0 indicates poor function, 100 indicates unaffected function.
      KOOS-Sport/RecSport and recreation domain of the knee injury and OA outcome score. 0 indicates no sport and recreation activity, 100 indicates unaffected sport and recreation activity.
      KOOS-QOLQuality of life domain of the knee injury and OA outcome score. 0 indicates poor quality of life, 100 indicates unaffected quality of life.
      Non-CE-MRIMOAKS-SynovitisSum score (0–6) of the Effusion-Synovitis (0–3) and Hoffa-Synovitis (0–3) subscales of the MRI in OA Knee Score (MOAKS)
      CE-MRIBLOKS-EffusionEffusion subscale (0–3) of the Boston–Leeds OA Knee score (BLOKS)
      CE-SynovitisThe whole-knee synovitis score (0–22) according to Guermazi et al.
      DCE-MRI (heuristic)Nvoxelvolume (ml) of voxels with “plateau” or “washout” patterns, i.e., the most perfused voxels
      ME × Nvoxel IRE × NvoxelAs a voxel represents a volume, Nvoxel can be regarded as the volume of the highest perfused synovium whereas the ME and IRE represent the degree of perfusion. By multiplying Nvoxel with the mean ME and mean IRE, respectively, we created two composite variables reflecting both the volume and degree of perfusion
      IRE × METhe product of the mean IRE and mean ME, as we believed that the two are the most defining TIC-parameters characterizing the perfusion profile of the voxels
      DCE-MRI (pharmacokinetic)KtransContrast transfer coefficient from blood to extracellular space over time (min−1) and thus a measure of capillary permeability
      VeProportion (between 0 and 1) of extra-vascular, extra-cellular space in the ROI
      iAUGC60Initial area under the gadolinium curve over 60 s
      Table IIBaseline characteristics and MRI outcome values from the mITT population (n = 91). Values are mean (standard deviation) unless otherwise stated
      Intervention armTotal sample
      Placebo (n = 46)Corticosteroid (n = 45)(n = 91)
      Female, no.31 (67.4%)26 (57.8%)57 (62.6%)
      Age65.7 (8.2)60.7 (9.9)62.2 (9.4)
      BMI29.1 (3.3)29.2 (3.9)29.2 (3.6)
      CRP
      Presented as median and [interquartile range].
      2.0 [0.5; 4.0](n = 37)2.0 [0.5; 5.0] (n = 40)2.0 [0.5; 5.0] (n = 77)
      KOOS-pain53.9 (15.7)52.6 (11.4)53.2 (13.7)
      KOOS-symptoms55.6 (19.5)58.5 (15.5)57.0 (17.6)
      KOOS-QOL37.9 (13.7)36.5 (12.8)37.2 (13.2)
      KOOS-ADL61.8 (18.4)60.1 (14.9)61.0 (16.7)
      KOOS-sport/recreation27.5 (18.7)30.1 (18.0)28.8 (18.3)
      Kellgren–Lawrence grade
      1, no.0 (0%)4 (8.9%)4 (4.4%)
      2, no.16 (34.86%)20 (44.4%)36 (39.6%)
      3, no.15 (32.6%)14 (31.1%)29 (31.9%)
      4, no.15 (32.6%)7 (15.6%)22 (24.1%)
      MOAKS-synovitis
      0, no.0 (0%)0 (0%)0 (0.0%)
      1, no.0 (0%)1 (2.2%)1 (1.1%)
      2, no.0 (0%)2 (4.4%)2 (2.2%)
      3, no.7 (15.2%)7 (15.6%)14 (15.4%)
      4, no.11 (23.9%)12 (26.7%)23 (25.2%)
      5, no.16 (34.8%)15 (33.3%)31 (34.1%)
      6, no.12 (26.1)8 (17.8%)20 (22.0%)
      CE-synovitis
      0–4, no.8 (17.4%)9 (20%)17 (18.7%)
      5–8, no.20 (43.5%)18 (40%)38 (42.7%)
      9–12, no.15 (32.6%)15 (33.3%)30 (33.0%)
      ≥13, no.3 (6.5%)3 (6.7%)6 (6.6%)
      BLOKS-effusion
      0, no.0 (0%)0 (0%)0 (0%)
      1, no.6 (13%)14 (31.1%)20 (22.0%)
      2, no.26 (56.5%)23 (51.1%)49 (53.8%)
      3, no.14 (30.4%)8 (17.5%)22 (24.2%)
      Nvoxel
      Presented as median and [interquartile range].
      49.39 [32.58; 80.12]50.20 [26.5; 59.65]50.02 [31.79; 70.36]
      ME × Nvoxel
      Presented as median and [interquartile range].
      90.77 [53.18; 134.45]84.28 [39.82; 111.39]87.20 [50.83; 125.33]
      IRE × Nvoxel
      Presented as median and [interquartile range].
      0.39 [0.22; 0.74]0.54 [0.10; 0.62]0.35 [0.19; 0.72]
      IRE × ME
      Presented as median and [interquartile range].
      0.01 [0.01; 0.02]0.01 [0.01; 0.02]0.01 [0.01; 0.02]
      Ktrans
      Presented as median and [interquartile range].
      0.02 [0.01; 0.04]0.02 [0.01; 0.04]0.02 [0.01; 0.04]
      Ve
      Presented as median and [interquartile range].
      0.26 [0.21; 0.32]0.26 [0.21; 0.34]0.26 [0.21; 0.33]
      iAUGC60
      Presented as median and [interquartile range].
      0.04 [0.03; 0.07]0.04 [0.02; 0.06]0.04 [0.03; 0.06]
      Ve: proportion of extravascular, extracellular space.
      Presented as median and [interquartile range].

      Statistics

      The statistical analyses were pre-specified to be conducted on the intention-to-treat population, i.e., all randomized patients (n = 100). However nine patients did not undergo DCE-MRI at baseline, wherefore the analyses were carried out on a modified intention-to-treat population (mITT; n = 91). Missing data were replaced using multiple imputations using age, gender, BMI, group allocation (masked) and baseline scores as predictors.
      The primary analysis was to compare the differences in the mean changes in the MRI-assessments of synovitis (both static and dynamic) from baseline to week 14 (primary endpoint) and week 26 between the two groups (corticosteroid vs placebo) (aim no. 1). We used repeated measures mixed linear models, including participants as a random effect, with fixed factors for group (2 levels) and week (2 levels (weeks 14 and 26)) and the corresponding interactions, adjusted for baseline values. Besides the implicit assumption that repeated measures within each individual are correlated, we applied the usual assumption of normality of the model residuals. To assess the associations between changes in synovitis on MRI and PROMs, simple bivariate correlations (Spearman) were performed, followed by linear regression with the PROMs as response and MRI-measures of synovitis as explanatory variables (aim no. 2). First, simple linear regression analyses were performed for each explanatory variable; from these analyses, only potential statistically significant MRI-variables (defined as P < 0.10) were included in a multiple regression analysis followed by further adjustment for age, gender, BMI and group allocation. All MRI-variables underwent the same analyses. For sensitivity purposes, we performed the same analyses on a sub-group of participants who had definite MRI-based synovitis, i.e., a baseline CE-Synovitis (whole-knee CE-MRI knee score) score > 4, thus excluding participants with normal/equivocal synovitis as defined by Guermazi et al.
      • 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.
      . ICCs were calculated for all MRI-variables. All statistical analyses were pre-specified in a sub-study protocol made available online from www.parkerinst.dk on January 17, 2016. Statistical significance was accepted at P < 0.05 and SAS statistical software (v. 9.3) was used for all statistical analyses.

      Results

      Ninety-one of the 100 randomized participants had complete DCE-MRI data at baseline (46 in the placebo group and 45 in the corticosteroid group) and constituted the mITT. Of these, 78 participants completed the first follow-up (week 14) and 63 completed the study, i.e., DCE-MRI data at baseline, and weeks 14 and 26. The trial profile and reasons for exclusion at all time points are shown in Fig. 2.
      Fig. 2
      Fig. 2Trial profile. *mITT (n = 91); Ø: circumference.
      The placebo-group was on average older (mean difference: 5.1 years; 95% CI: 1.3–8.8) and had a higher baseline BLOKS-Effusion score (mean difference: 0.31; 95% CI: 0.03–0.59) and KL-grade (mean difference: 0.4; 95% CI: 0.1–0.8). The two groups did not differ otherwise at baseline (Table I). Eighteen participants (ten in the placebo and eight in the corticosteroid group) underwent joint aspiration at baseline, nine (five in the placebo, four in the corticosteroid group) at week 14 and six (one in the placebo, five in the corticosteroid group) at week 26.

      Changes in MRI-measures of synovitis (placebo vs corticosteroid)

      DCE-MRI

      There were no statistically significant differences between groups in the mean changes in ME × Nvoxel (major outcome) or the remaining DCE-MRI variables neither at week 14 nor week 26 (Table III, Table IV).
      Table IIIComparison of changes in outcome measures at the main trial end-point (week 14)
      Change from baseline, week 14Intervention armComparison
      PlaceboCorticosteroidMean difference (95% CI)P-value
      ME × Nvoxel−1.77 (−15.26–11.73)−7.36 (−21.01–6.29)5.60 (−13.63–24.83)0.57
      Nvoxel−0.16 (−7.16–6.84)−9.18 (−16.26–−2.10)9.02 (−0.95–18.99)0.08
      IRE × Nvoxel−0.047 (−0.169–0.075)−0.018 (−0.142–0.105)−0.03 (−0.20–0.15)0.74
      IRE × ME−0.001 (−0.004–0.002)0.000 (−0.003–0.003)−0.001 (−0.005–0.003)0.61
      Ktrans0.003 (−0.003–0.010)0.000 (−0.006–0.007)0.003 (−0.006–0.012)0.54
      Ve−0.001 (−0.034–0.019)0.013 (−0.013–0.040)−0.021 (−0.058–0.017)0.27
      iAUGC60−0.003 (−0.012–0.006)0.002 (−0.008–0.011)−0.005 (−0.018–0.008)0.45
      MOAKS-Synovitis0.03 (−0.19–0.25)−0.38 (−0.61–−0.16)0.41 (0.09–0.73)0.01
      P = 0.35 for interaction (week*group).
      CE-Synovitis−0.50 (−1.18–0.18)−0.91 (−1.60–−0.23)0.42 (−0.55–1.38)0.40
      BLOKS-Effusion0.00 (−0.14–0.14)−0.09 (−0.23–0.05)0.09 (−0.11–0.29)0.38
      CRP0.54 (−0.62–1.70)−0.94 (−2.06–0.17)1.48 (−0.13–3.10)0.07
      KOOS-Pain14.8 (10.6–18.9)14.4 (10.1–18.6)0.4 (−5.5–6.3)0.89
      KOOS-Sport/Recreation14.4 (9.0–19.8)17.3 (11.8–22.8)−2.9 (−10.6–4.8)0.46
      KOOS-Symptoms12.0 (8.1–16.0)14.0 (10.0–18.0)−2.0 (−7.6–3.6)0.48
      KOOS-QOL8.4 (4.2–12.5)10.1 (5.9–14.3)−1.7 (−7.6–4.2)0.58
      KOOS-ADL14.7 (10.8–18.6)15.4 (11.5–19.4)−0.7 (−6.2–4.8)0.80
      Ve: proportion of extravascular, extracellular space
      P = 0.35 for interaction (week*group).
      Table IVComparison of changes in outcome measures at the follow-up (week 26)
      Change from baseline, week 26Intervention armComparison
      PlaceboCorticosteroidMean difference (95% CI)P-value
      ME × Nvoxel−3.27 (−16.76–10.22)−3.83 (−17.47–9.82)0.56 (−18.67–19.79)0.95
      Nvoxel1.87 (−5.13–8.87)−5.91 (−12.99–1.17)7.78 (−2.19–17.75)0.13
      IRE × Nvoxel−0.114 (−0.237–0.008)0.056 (−0.067–0.180)−0.171 (−0.219–0.070)0.31
      IRE × ME−0.001 (−0.003–0.002)0.002 (−0.001–0.005)−0.003 (−0.006–0.001)0.25
      Ktrans0.002 (−0.004–0.009)−0.001 (−0.007–0.006)0.003 (−0.006–0.012)0.50
      Ve0.024 (−0.002–0.051)0.022 (−0.004–0.049)0.002 (−0.035–0.039)0.91
      iAUGC60−0.003 (−0.012–0.006)0.004 (−0.006–0.013)−0.006 (−0.019–0.007)0.35
      MOAKS-Synovitis0.12 (−0.11–0.34)−0.45 (−0.68–−0.23)0.57 (0.25–0.89)0.0006
      P = 0.35 for interaction (week*group).
      CE-Synovitis−0.78 (−1.46–−0.10)−0.80 (−1.49–−0.12)0.02 (−0.94–0.99)0.96
      BLOKS-Effusion0.04 (−0.10–0.18)−0.02 (−0.16–0.12)0.07 (−0.14–0.27)0.52
      CRP0.04 (−1.12–1.20)−0.26 (−1.38–0.85)0.30 (−1.31–1.92)0.71
      KOOS-Pain15.4 (11.2–19.6)14.2 (10.0–18.4)1.2 (−4.7–7.2)0.68
      KOOS-Sport/Recreation15.2 (9.8–20.6)14.3 (8.8–19.8)0.9 (−6.9–8.6)0.82
      KOOS-Symptoms13.5 (9.5–17.4)12.2 (8.2–16.2)1.3 (−4.4–6.9)0.65
      KOOS-QOL10.6 (6.4–14.7)14.6 (10.4–18.8)−4.1 (−10.0–1.9)0.18
      KOOS-ADL15.7 (11.9–19.6)14.8 (10.8–18.7)1.0 (−4.6–6.5)0.73
      Ve: proportion of extravascular, extracellular space.
      P = 0.35 for interaction (week*group).

      Static MRI

      There were no other differences between groups in the static MRI-variables, except for the mean change from baseline in MOAKS-Synovitis at both week 14 (mean difference: 0.41, 95% CI: 0.09–0.73, P = 0.01) and week 26 (mean difference: 0.57, 95% CI: 0.25–0.89, P < 0.001) in favor of intra-articular corticosteroids; however, the Group*Week interaction was not statistically significant (P = 0.35) (Table III, Table IV).

      Associations between PROMs and MRI

      KOOS-Pain

      Among all MRI-variables only change in CE-Synovitis was statistically significantly correlated with the change in KOOS-Pain at week 26 (r = −0.36) (Table V). No changes in any MRI-variables at week 14 were statistically significantly correlated with the corresponding change in KOOS-Pain.
      At week 14, no potentially statistical significant explanatory variables (P < 0.10) were found in the simple regression analyses. At week 26, change in CE-Synovitis was the only statistical significant explanatory variable of change in KOOS-Pain in the multiple regression analyses (Table VI).

      KOOS-ADL

      Among all MRI-variables only changes in CE-Synovitis were statistically correlated with KOOS-ADL at both week 14 (r = −0.21) and 26 (r = −0.27) (Table V).
      Change in CE-Synovitis was the only statistically significant explanatory variable of KOOS-ADL at week 14, but not after adjustment for age, gender, BMI, and group. At week 26, CE-Synovitis remained statistically significant also after adjustment (Table VI).

      KOOS-Sport/Recreation

      Changes in CE-Synovitis (r = −0.25), Nvoxel (r = −0.25) and IRE × Nvoxel (r = −0.29) were correlated to changes in KOOS-Sport/Recreation at week 26 (Table V). The regression analyses revealed no statistical significant explanatory variables at any of the time points (Table VI).

      KOOS-Symptoms

      Changes in CE-Synovitis was correlated with changes in KOOS-Symptoms at week 14 (r = −0.21) and 26 (r = −0.25); change in iAUGC60 was also statistically significantly correlated (r = −0.25) at week 26 (Table V).
      No MRI-variables were statistically significant explanatory variables in the multiple regression analyses, neither at week 14 nor week 26 (Table VI).

      KOOS-QOL

      Changes in KOOS-QOL were statistically significantly correlated with changes in ME × Nvoxel (r = −0.29) and Nvoxel (r = −0.34) at week 14 and changes in CE-Synovitis (r = −0.23) at week 26 (Table V). The multiple regression analyses revealed no statistically significant MRI-explanatory variables of KOOS-QOL (Table VI).
      Table VSpearman's rank correlation matrix of changes from baseline to week 14 and week 26 (italic). *P < 0.05; **P < 0.01
      CE-SynovitisBLOKS-EffusionMOAKS-SynovitisNvoxelME × NvoxelIRE × NvoxelIRE × MEKtransVeiAUGC60
      CE-Synovitis1.00
      BLOKS-Effusion0.32**1.00
      0.36**
      MOAKS-Synovitis0.190.66**1.00
      0.200.54**
      Nvoxel0.31**0.39**0.40**1.00
      0.62**0.22*0.32**
      ME × Nvoxel0.32**0.36**0.32**0.89**1.00
      0.57**0.33**0.26*0.83**
      IRE × Nvoxel0.41**0.170.110.61**0.72**1.00
      0.49**0.30**0.130.72**0.71**
      IRE × ME0.23*0.24*0.140.39**0.54**0.70**1.00
      0.42**0.37**0.29**0.47**0.68**0.72**
      Ktrans0.45**0.23*0.150.28**0.38**0.52**0.59**1.00
      0.31**0.180.180.36**0.30**0.37**0.34**
      Ve−0.32**−0.15−0.15−0.30**−0.29**−0.38**−0.42**−0.53**1.00
      0.26*0.24*0.39**0.31**0.33**0.32**0.41**0.47**
      iAUGC600.30**0.29**0.150.32**0.38**0.54**0.66**0.68**−0.51**1.00
      0.36**0.24*0.130.46**0.55**0.61**0.63**0.50**0.43**
      KOOS-Pain−0.17−0.090.04−0.19−0.19−0.09−0.080.06−0.01−0.09
      0.36**0.100.040.110.130.160.090.030.040.19
      KOOS-Sport/Rec−0.070.00−0.02−0.17−0.14−0.11−0.09−0.030.07−0.06
      0.25*0.110.070.25*0.160.29**0.110.120.110.19
      KOOS-Symptoms−0.21*−0.090.00−0.17−0.17−0.16−0.11−0.02−0.10−0.12
      0.25*0.020.760.190.160.170.090.100.000.25*
      KOOS-QOL−0.17−0.15−0.03−0.34**−0.29**−0.16−0.09−0.030.070.00
      0.23*0.090.160.150.140.100.030.110.190.07
      KOOS-ADL−0.21*−0.100.02−0.08−0.08−0.15−0.09−0.040.06−0.12
      0.27*0.140.040.150.150.190.120.010.070.15
      Table VIRegression analyses (KOOS as outcome and MRI as predictor variables) with regression coefficients and 95% CI (). Adjustment for age, gender, BMI and group allocation
      Week 14 (Δ from baseline)Simple regression, potential predictors (P < 0.10)Multiple regression, significant predictors (P < 0.05)Adjusted multiple regression, significant predictors (P < 0.05)
      KOOS-PainN/AN/AN/A
      KOOS-Sport/RecN/AN/AN/A
      KOOS-SymptomsME × Nvoxel

      Nvoxel
      −0.05 (−0.10; 0.00)

      −0.11 (−0.22; 0.00)
      N/AN/A
      KOOS-QOLCE-Synovitis

      BLOKS-Effusion

      Nvoxel

      ME × Nvoxel
      −1.16 (−2.37; 0.05)

      −4.95 (−10.44; 0.54)

      −0.14 (−0.24; −0.04)

      −0.05 (−0.10; 0.00)
      N/AN/A
      KOOS-ADLCE-Synovitis−1.06 (−2.29; 0.17)N/AN/A
      Week 26 (Δ from baseline)Simple regression, potential predictors (P < 0.10)Multiple regression, significant predictors (P < 0.05)Adjusted multiple regression, significant predictors (P < 0.05)
      KOOS-PainCE-Synovitis

      Nvoxel

      ME × Nvoxel

      iAUGC60
      −2.17 (−3.38; −0.96)

      −0.11 (−0.22; 0.00)

      −0.06 (−0.12; 0.00)

      −87.27 (−183.64; 9.07)
      CE-Synovitis−2.24 (−3.85;−0.63)CE-Synovitis−2.16 (−3.80; −0.52)
      KOOS-Sport/RecCE-Synovitis

      Nvoxel

      IRE × Nvoxel
      −1.48 (−2.98; 0.02)

      −0.12 (−0.25; 0.01)

      −6.25 (−12.60; 0.10)
      N/AN/A
      KOOS-SymptomsCE-Synovitis

      Nvoxel

      iAUGC60
      −1.80 (−3.18; −0.42)

      −0.10 (−0.22; 0.02)

      −130.86 (−236.49; −25.23)
      N/AN/A
      KOOS-QOLCE-Synovitis−1.34 (−2.57; −0.11)CE-Synovitis−1.34 (−2.57; −0.11)N/A
      KOOS-ADLCE-Synovitis−1.60 (−2.80; −0.40)CE-Synovitis−1.60 (−2.80; −0.40)CE-Synovitis−1.46 (−2.71; −0.21)
      Δ: Change.

      Sensitivity analyses

      The subgroup with CE-Synovitis > 4 consisted of 74 persons (38 in the placebo group, 36 in the corticosteroid group) and were on average 6.6 years older (standard deviation (SD): 9.0) with more pain (9.5 points lower KOOS-Pain, SD: 13.5) and worse function in Sports and Recreation (9.9 lower KOOS-Sport/Rec, SD: 18.4) compared to the low-synovitis group. There was no difference in gender and BMI between the low and high synovitis groups. As expected, all the static and DCE-MRI variables, with the exception of Ktrans (no difference) were statistically higher in the high-synovitis group.
      As in the main analyses, there was a statistical significant difference in MOAKS-synovitis in favor of corticosteroid at both week 14 and 26 but still no interaction (Supplemental file 2). There were no group differences in the remaining MRI-variables. The regression analyses at week 14 confirmed the previous results.

      Discussion

      This study was designed to compare intra-articular corticosteroids with saline administered before an exercise intervention on synovitis assessed with MRI. Overall, there were no statistically significant differences between the two interventions in regards of MRI-measures of synovitis. This may be due to the relatively long follow-up of 14 weeks. The anti-inflammatory and clinical effects of corticosteroids are short-lived and a follow-up of one-two weeks would have been more appropriate in order to detect an effect on MRI, especially as DCE-MRI parameters are known to be sensitive to change
      • 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.
      • Wenham C.Y.
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      • et al.
      The responsiveness of novel, dynamic, contrast-enhanced magnetic resonance measures of total knee synovitis after intra-articular corticosteroid for painful osteoarthritis.
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      • et al.
      Dynamic contrast-enhanced, extremity-dedicated MRI identifies synovitis changes in the follow-up of rheumatoid arthritis patients treated with rituximab.
      . In addition, the 40 mg methylprednisolone used in our study are in the lower range of the recommended dosage. Three recent knee OA-studies found a decrease in MRI-measures of synovitis following an injection with 80 mg methylprednisolone with a median time between baseline and follow-up MRI of 8
      • 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.
      • 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).
      and 20
      • Wenham C.Y.
      • Balamoody S.
      • Grainger A.J.
      • Hensor E.M.
      • 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.
      days, respectively. While these studies indicate a short term effect, all three studies were observational and contrast our randomized controlled trial. Nevertheless, our study design precludes any conclusions on changes occurring within the first weeks after injection.
      At the first follow-up however, there was an indication that Nvoxel, the volume of the most perfused synovium, as well as CRP diminished more in the corticosteroid group (Table II). Even though the group differences did not reach statistical significance, the estimates and 95% confidence intervals suggest a potential beneficial effect that needs further exploration.
      The group differences in MOAKS-Synovitis at both weeks 14 and 26, in favor of corticosteroids, indicate that corticosteroids in combination with exercise might have a potential beneficial effects on synovitis. However, the result is difficult to interpret as the semi-quantitative non-CE-MRI MOAKS-Synovitis in theory should be less sensitive than the more refined DCE-MRI measures as indicated in previous studies
      • Wenham C.Y.
      • Balamoody S.
      • Grainger A.J.
      • Hensor E.M.
      • 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.
      • Boesen M.
      • Kubassova O.
      • Cimmino M.A.
      • Ostergaard M.
      • Taylor P.
      • Danneskiold-Samsoe B.
      • et al.
      Dynamic contrast enhanced MRI can monitor the very early inflammatory treatment response upon intra-articular steroid injection in the knee joint: a case report with review of the literature.
      • Cimmino M.A.
      • Parodi M.
      • Zampogna G.
      • Boesen M.
      • Kubassova O.
      • Barbieri F.
      • et al.
      Dynamic contrast-enhanced, extremity-dedicated MRI identifies synovitis changes in the follow-up of rheumatoid arthritis patients treated with rituximab.
      . This may also be due to a statistical power issue, as the sample size calculations in the hosting study were based on changes in KOOS-Pain and not MRI-measures. This may have influenced the results in general and constitute an important limitation of this sub-study. In addition, our sub-study included several statistical analyses and although they were all pre-specified, the risk of chance findings (type I errors) is not negligible.
      Synovitis has been shown to be a risk factor of structural progression and TKA
      • Roemer F.W.
      • Zhang Y.
      • Niu J.
      • Lynch J.A.
      • Crema M.D.
      • Marra M.D.
      • et al.
      Tibiofemoral joint osteoarthritis: risk factors for MR-depicted fast cartilage loss over a 30-month period in the multicenter osteoarthritis study.
      • 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?.
      • Felson D.T.
      • Niu J.
      • Neogi T.
      • Goggins J.
      • Nevitt M.C.
      • Roemer F.
      • et al.
      Synovitis and the risk of knee osteoarthritis: the MOST Study.
      • Roemer F.W.
      • Kwoh C.K.
      • Hannon M.J.
      • Hunter D.J.
      • Eckstein F.
      • Wang Z.
      • et al.
      Can structural joint damage measured with MR imaging be used to predict knee replacement in the following year?.
      . This may justify the use of intra-articular corticosteroids, not only as an analgesic but also as a synovitis-reducing anti-inflammatory. Our results however cannot confirm these notions and are thus in concordance with the main study report
      • Henriksen M.
      • Christensen R.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Ellegaard K.
      • et al.
      Evaluation of the benefit of corticosteroid injection before exercise therapy in patients with osteoarthritis of the knee: a randomized clinical trial.
      and the report on US outcomes
      • Henricsdotter C.
      • Ellegaard K.
      • Klokker L.
      • Bartholdy C.
      • Bandak E.
      • Bartels E.M.
      • et al.
      Changes in ultrasound assessed markers of inflammation following intra-articular steroid injection combined with exercise in knee osteoarthritis: exploratory outcome from a randomized trial.
      showing no differences between the two interventions neither in regards of PROMs nor in US-measures of synovial inflammation.
      An overall decrease in synovitis assessed on CE-MRI (CE-Synovitis) in both groups was observed at week 26 (and week 14 for the corticosteroid group). Even though reduction of synovitis on US following intra-articular placebo has been described
      • Hall M.
      • Doherty S.
      • Courtney P.
      • Latief K.
      • Zhang W.
      • Doherty M.
      Ultrasound detected synovial change and pain response following intra-articular injection of corticosteroid and a placebo in symptomatic osteoarthritic knees: a pilot study.
      , we believe that this effect is due to the exercise program rather than the intra-articular injections. This indicates a synovitis-reducing effect of exercise that persists even 12 weeks after the termination of the program. It has been suggested that exercise may have a (biochemical) anti-inflammatory effect
      • Petersen A.M.
      • Pedersen B.K.
      The anti-inflammatory effect of exercise.
      but whether exercise also has a beneficial effect on synovitis and not only pain and function in knee OA needs to be confirmed in future studies.
      In the second part of the analyses, we investigated the associations between changes in PROMs and MRI-measures of synovitis. At week 14, the primary endpoint, we found no statistical significant MRI-explanatory variables of either of the PROMs. At week 26, change in CE-Synovitis was predictive of changes in KOOS-Pain and KOOS-ADL indicating that a one-point decrease in CE-Synovitis associates with an improvement of 2.1 and 1.5 points in KOOS-Pain and KOOS-ADL, respectively. It is interesting to notice that the effects of CE-Synovitis first become evident at week 26—this may however also be due to multiple statistical tests and chance findings.
      The lack of including other known sources of pain such as bone marrow lesions is an important limitation that may have influenced the results of this sub-study. However, MRI-images provide an abundance of information and due to factors such as time and funding a complete analysis of all OA-relevant aspects of MR-images was not feasible in this study. The lack of inter-reader reliability analyses also constitutes an important limitation. Important strengths to this study include the rigorous study design and pre-specified statistical analysis plan and the assessment of synovitis using three different MRI-techniques.
      In conclusion, our study does not justify the use of intra-articular corticosteroids over intra-articular saline when combined with an exercise program, for reduction of synovitis in knee OA. The improvement in pain and function following the intervention with intra-articular corticosteroids/saline and exercise could not be explained by a decrease in synovitis on MRI indicating other pain causing/relieving mechanisms in knee OA.

      Author contribution

      All authors revised the manuscript and approved the final version. RR performed all MRI analyses, contributed to the study design, statistical design and analysis, analysis and interpretation of the data, and drafted the manuscript. MH contributed to the study design, statistical design and analysis and interpretation of the data. CB supervised all exercise sessions, contributed to the study design and interpretation of the data. KE performed all intra-articular injections, contributed to the study design and interpretation of the data. LK, EB, BBH, HB contributed to the study design, analysis and interpretation of the data. MB contributed to the study design, radiological supervision, analysis and interpretation of the data. MB takes responsibility for the integrity of the work as a whole, from inception to final draft.

      Competing interests

      MB is chairman of the medical and scientific board, Image Analysis Ltd., London, UK, from which he has received fees/honoraria (<$10,000) covering travel/accommodation costs as well as a small yearly honorarium. All other authors have nothing to disclose.

      Role of the funding source

      The funding sources had no role in the study design, data collection and analysis, interpretation or reporting of this work, or the decision to submit the work for publication. All authors are independent of the funding sources.

      Acknowledgements

      The authors would like to thank the Danish Council for Independent Research (10-093704), Oak Foundation, Association of Danish Physiotherapists, Lundbeck Foundation and Capital Region of Denmark for the opportunity to conduct this study.

      Appendix A. Supplementary data

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