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Hip Inflammation MRI Scoring System (HIMRISS) to predict response to hyaluronic acid injection in hip osteoarthritis
Accepted Manuscript Title: Hip Inflammation MRI Scoring System (HIMRISS) to predict response to hyaluronic acid injection in hip osteoarthritis Author: Nicolas Deseyne Thierry Conrozier Henri Lellouche Bernard Maillet Ulrich Weber Jacob L. Jaremko Joel Paschke Jonathan Epstein Walter P. Maksymowych Damien Loeuille PII: DOI: Reference:
S1297-319X(17)30158-6 http://dx.doi.org/doi:10.1016/j.jbspin.2017.08.004 BONSOI 4627
To appear in: Received date: Accepted date:
28-6-2017 31-8-2017
Please cite this article as: Deseyne N, Conrozier T, Lellouche H, Maillet B, Weber U, Jaremko JL, Paschke J, Epstein J, Maksymowych WP, Loeuille D, Hip Inflammation MRI Scoring System (HIMRISS) to predict response to hyaluronic acid injection in hip osteoarthritis, Joint Bone Spine (2017), http://dx.doi.org/10.1016/j.jbspin.2017.08.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Hip Inflammation MRI Scoring System (HIMRISS) to predict response to hyaluronic acid injection in hip osteoarthritis.
Jacob L. Jaremko f, Joel Paschkeg, Jonathan Epstein
h,
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Nicolas Deseynea, Thierry Conrozier b, Henri Lellouche c, Bernard Maillet d, Ulrich Weber e, Walter P. Maksymowych I, Damien
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Loeuille a
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a - Department of Rheumatology, CHRU de Nancy, 54500 Vandoeuvre les Nancy, France
b - Department of Rheumatology, North Hospital Franche-Comté, 25200 Montbéliard, France
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c - Department of Rheumatology, Lariboisière Hospital, 75475 Paris cedex 10, France d - Department of Rheumatology, Clinique Saint Odilon, 03000 Moulins, France
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e - King Christian 10th Hospital for Rheumatic Diseases, Gråsten, Denmark, and Institute of Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark
d
f - Dept. of Radiology and Diagnostic Imaging, University of Alberta, Edmonton, AB T6G 2R3, Canada
Canada
Ac ce pt e
g - CaRE Arthritis, Edmonton, Alberta T6W 2Z8, Canada.
h - CEC-Inserm CIE6, Epidemiology and Clinical Evaluations Department, CHRU Nancy, 54500 Vandoeuvre les Nancy, France
i - Department of Medicine, University of Alberta, Edmonton, Edmonton, Alberta, AB T6G 2R3, Canada.
Corresponding Author: Dr Nicolas Deseyne, [email protected] Service de Rhumatologie, CHRU Nancy, 5 Rue du Morvan, 54500 Vandœuvre-lès-Nancy
Abstract
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Objective: To assess predictors of response, according to hip MRI inflammatory scoring system (HIMRISS), in a sample of patients with hip osteoarthritis (OA) treated by hyaluronic acid (HA) injection. Method: 60 patients with hip OA were included. Clinical outcomes were assessed at baseline
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and three months after HA injection by WOMAC. On hip MRI performed before HA injection, bone marrow lesion (BML) and synovitis were assessed by HIMRISS by four
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readers. The inter-reader reliability of HIMRISS was for HIMRISS total, acetabular BML,
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femoral BML and synovitis-effusion respectively 0.86, 0.64, 0.83 and 0.78. Associations between MRI features and clinical data were assessed. Logistic regression (univariate and
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multivariate) was used to explore associations between MRI features and response to HA injection, according to WOMAC50 response at three months.
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Results: 45.5% of patients met WOMAC50 response. Five adverse events were reported. At baseline, WOMAC-function correlated significantly to HIMRISS synovitis-effusion (r=0.27,
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p=0.03). In univariate analysis, BML femoral according to binary assessment (p=0.025),
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HIMRISS BML femoral (p=0.0038), HIMRISS BML acetabular (p=0.042), HIMRISS total (p=0.0092) were associated negatively with WOMAC50 response. In multivariate analysis, adjusted for age and BMI, HIMRISS femoral BML (p=0.02) and HIMRISS total (p=0.016) were negatively associated with response. At a HIMRISS threshold of <15, 82% of patients were responders, with specificity SP=0.97, sensitivity SN=0.39, and positive and negative predictive values of 0.91 and 0.64 respectively. Conclusion: HIMRISS is reliable for total scores and sub-domains. It permits identification of responders to HA injection in hip OA patients. Key Words : Osteoarthritis, hip, magnetic resonance imaging (MRI), bone marrow lesion, synovitis, HIMRISS, hyaluronate acid.
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ip t cr us an M d Ac ce pt e Introduction
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Osteoarthritis (OA) of the hip is common and potentially debilitating, with a prevalence of 3– 9 % in Western populations (1,2). It is the major reason for approximately 200,000 total hip replacements performed annually in the United States (3), and contributes significantly to the $185 billion estimated annual cost of OA (4). Hip OA was also shown to be associated with
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an increased risk of all-cause and cardiovascular mortality among older white women (5). The American College of Rheumatology (ACR) and Osteoarthritis Research Society International
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(OARSI) have defined clinical and radiographic criteria to standardize diagnosis and
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radiographic grading of hip OA (6,7). Magnetic resonance imaging (MRI) is more sensitive to early subtle tissue abnormalities (8) but its place remains limited in clinical practice (9).
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Recently, MRI scoring systems have been developed and validated which adopt a semi quantitative approach to assess various active and structural abnormalities in hip OA (10–15).
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Among all MRI features in OA, bone marrow lesion (BML) and synovitis show highest
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association (16–20).
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correlations to hip pain (10). Concerning joint damage progression, only BML showed an
Concerning treatment response, only one study has compared the performance of HIMRISS and Hip Osteoarthritis MRI Scoring System (HOAMS) to evaluate the efficacy of intraarticular glucocorticoid injection on BML and synovitis in hip OA patients (10). Both scores demonstrated association between pain and MRI activity features at baseline, but the decrease of BML score was not correlated with pain improvement at week 12 for either system, whether decrease of synovitis was observed and was correlated with pain improvement.
Three scores, HOAMS, Scoring Hip Osteoarthritis with MRI (SHOMRI) and HIMRISS, assess BML and synovitis-effusion with excellent and good intra- and inter-reader reliabilities, respectively (10,11,18). For our study, HIMRISS was favoured because unlike
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HOAMS it did not require intravenous contrast injection, and SHOMRI was not published in full text before the beginning of this study. The primary objective of this study was to determine the MRI features predictive of response to viscosupplementation injection in a population of 60 patients with hip OA. The secondary goals were to determine the
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relationship between MRI features and hip symptoms, and to compare MRI lesion patterns
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and severity between injected versus non-injected hips.
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Patients and methods
The PREVICOX study is a prospective multicenter (40 study centers) (21) study, which aims
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to assess predictive factors (clinical and imaging) of response after intra-articular hyaluronate
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(HA) injection in patients with hip OA. The study was conducted in France, from November
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2013 to March 2015. This study was recorded at EudraCT, number 2013-A00165-40 in respect to the principles of Good Clinical Practice (GCP), and the Declaration of Helsinki concerning medical research in humans and the country-specific regulations. Before enrollment, patients were required to sign an informed consent form. The consent form and protocol, which complied with the requirements of the International Conference on Harmonization (ICH), were reviewed and approved by a French committee of ethic (Comité consultatif sur le traitement de l'information en matière de recherche scientifique (CCTIRS)). It was registered 31 January 2013 under the N° ID RCB 2013-A00165-40.
The inclusion criteria were:
Symptomatic Hip OA meeting ACR criteria (6), inadequate
response to NSAIDs or oral analgesic therapy. All patients had pelvic MRI examination performed before hip injection. Exclusion criteria were: allergy or known hypersensitivity to
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HA or mannitol, contraindication to hip injection, total hip replacement scheduled in the next three months, intra articular injection of corticosteroid the past month or injection of HA the past three months in targeted hip, patients with systematic or regional musculo-skeletal conditions (Rheumatoid Arthritis, Spondylarthritis, Lupus, Psoriasic arthritis, Paget’s disease,
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gout, sciatalgia), clinically relevant comorbidities (advanced and/or unstable cardiovascular pulmonary, neurological, haematology and endocrinopathy disorders, diabetes), and
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pregnancy.
Data collected at inclusion comprised: age, sex, height, weight, unilateral or bilateral hip
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osteoarthritis, the side of the symptomatic hip, symptom duration, type and quantity of oral medications used for hip OA (e.g. pain killer, NSAID, disease modifying anti osteoarthritic
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drug (DMOAD)), use of physiotherapy, previous corticosteroid and/or acid hyaluronic
contralateral and targeted hip.
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injection in the hip, surgical history: contralateral hip replacement, arthroscopy of
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Pain, stiffness and function were assessed by the Western Ontario & McMaster (WOMAC) questionnaire (22) (pain, stiffness, function) and global health assessment on a visual analogic scale (VAS) at inclusion and 12 weeks after intra-articular hyaluronate injection. Adverse events (AEs) were collected at each visit and categorized using the Medical Dictionary for Regulatory Activities (MedDRA). Definition of adverse events (AEs) and serious adverse events (SAEs) were in accordance with the European standard EN ISO 14155: 2011. Investigators had to note all AEs on the report form.
The response to the HA injection was defined by a high improvement on OARSI-OMERACT criteria (23). Responders presented an improvement of WOMAC Pain and/or WOMAC Function> 50% with an absolute value of change >20 UI.
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Hip injection was performed according to fluoroscopic or ultrasonographic procedures with HAnox-M-XL
(marketed
as
HAppyCross®,
LABRHA
SAS,
Lyon,
France),
a
viscosupplement that combines a high molecular weight, cross-linked sodium hyaluronate of
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non-animal origin (16 g/l) with mannitol (35 g/l) (oxygen free radicals neutralization (24)),
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supplied in a ready-to-use 2.2 ml syringe.
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MRI protocol:
All 60 patients had coronal T1 and T2 sequences. 56 patients had a pelvic MRI, and 4 patients
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only unilateral hip MRI assessment. In total, all patients had at least two planes of acquisition in MRI, and 27 (45%) had three-dimensional examination.
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All patients received a coronal fluid-sensitive MRI sequence: 26 patients had STIR sequences, 34 T2-FS (fat saturated), with slice thickness (3-5.5 mm), matrix size (256x256-456x402),
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and a wide FOV limited to the pelvic region. This MRI protocol satisfied OARSI
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recommendations (25). All MRI were scored by four readers including three rheumatologists (two seniors (DL, UW), one junior (ND)) and one senior radiologist (JJ), blinded to clinical information.
MRI assessment:
-Firstly a binary assessment was performed on synovitis-effusion, BML femoral and acetabular, and a lesion was noted as present or absent if at least two of the three seniors readers agreed. -Secondly a semi-quantitative approach was performed, according to the HIMRISS method. Reading was performed by the four readers after a minimal calibration on an e-learning module, and hips were scored on a web-based overlay integrated with a web-based DICOM
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viewer designed for use with DICOM MR images of the hip (26). By dragging with a mouse the overlay was positioned over the largest diameter of the femoral head and resized to ensure alignment with the subchondral bone. On pelvic MRI, both hips were scored, blindly to the targeted hip.
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The HIMRISS method was applied according to the following manner (27): presence or absence of BML in each of the sectors is scored dichotomously directly on the image display.
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The central 5 slices (centered on the “central slice”) show most of the head volume (figure 1
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Legend of the figure 1: A. Example of BML on the right femoral head (white arrow). B. This BML is located in sector “1” and is scored as “1” (white arrow). C. Example of synovitis-
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effusion on the right hip: the black arrow annotates the maximal depth of fluid perpendicular to the long axis (white line) of the fluid collection, 5 mm in extent (grade 2). ). In each of
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these slices, 9 sectors are defined, 8 around a clock face (starting superomedially) and the last central. For up to 5 remaining anterior slices containing femoral head, pair of regions
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(anterior-superior, anterior-inferior) is formed. This is also done for up to 5 posterior slices.
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Thus the femoral BML score varied from 0 to 65 points. BML of the acetabulum is assessed in the central 5 slices as described above, the acetabulum is divided into 3 regions containing a similar volume of sub - articular bone. In up to 5 slices anterior to the central slices, acetabulum is scored in 2 regions each (superior and inferior), and this is repeated for up to 5 slices posterior to central slices. The acetabular BML score ranged from 0 to 35 points. Total BML score varied from 0 to 100.
Synovitis and effusion score are scored in 2 locations according to a grading scheme (0-2) that reflects thickness of synovitis-effusion (Grade 0: < 2 mm, grade 1: 2–4 mm, grade 2:> 4 mm). The maximum combined thickness of synovium and fluid contacting the femur, perpendicular to the bone, was measured and this was repeated in each of the same 15 slices used for
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acetabular scoring (figure 1). The effusion-synovitis score ranged from 0 to 30. Finally, the total HIMRISS score is ranged from 0 to 130.
To establish the mean HIMRISS score of each patient, the scores of the three senior readers
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(with at least ten years of imaging experience in musculo-skeletal diseases) and the junior reader were used. Inter reader reliability (n=4) for HIMRISS was excellent for BML femoral
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and total score, with ICC [95% CI], 0.83[0.78-0.87] and 0.86 [0.81-0.89], and good for
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acetabular BML and synovitis-effusion, at 0.64 [0.52-0.74] and 0.78 [0.65-0.86] respectively.
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There was no difference between the three senior readers and the junior reader.
Statistical analysis
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A descriptive analysis was performed for clinical and imaging data. Qualitative variables were
using mean and standard deviation.
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described using absolute numbers and percentages. Quantitative variables were described
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Differences regarding injected versus non-injected hip on MRI, and predictive factors of response were analyzed using univariate and/or multivariate comparison (CHI² or Fischer’s exact test, Mann and Whitney test) regarding clinical characteristics and MRI features of the patients. HIMRISS score was used as an outcome in linear regression with a stepwise model. P<0.05 was considered statistically significant. The statistical analysis was carried out using SAS® version 9.1 (SAS Institute Inc., Cary, NC).
Results At baseline, 60 MRI were available for HIMRISS assessment, and 55 patients completed the follow-up examination (2 patients dropped from the study for joint hip replacement, and 3 patients for withdrawn).
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As shown in Table 1, patients presented severe disability (mean WOMAC function: 44.1/100) and severe painful hip OA (mean WOMAC pain: 49.2/100) with unilateral hip OA in 61.7% of the cases (n=37). On these 60 patients, 8.3% were classified Kellgren and Lawrence grade 1, 33.3% grade 2,
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31.7% grade 3 and 11.7% grade 4. 23 patients were known as presented a bilateral hip OA
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(38.3%) on the clinical evaluation.
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For WOMAC50 (pain and/or function), 45.5% were responders at three months to HA injection. Five adverse events were reported (8.3%). Two were classified as device/procedure
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AEs (3.3%). All 2 were described as an increase of the hip pain that occurred the very next hours after injection. One resolved in less than 24 hours with rest and paracetamol. One
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resolved in 1 week and needed NSAIDs. The other AES were low back pain (1 case), knee pain in patient with knee OA (1 case) and dizziness (1 case) and were considered as unrelated
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to the treatment and/or the procedure of injection.
Correlation between MRI features and patients’ symptoms at baseline: No association was found between MRI activity features and patient symptoms, except for a fair correlation (ICC 0.27) between HIMRISS synovitis-effusion and WOMAC-function at baseline (p=0.03).
There was no association between MRI features (binary assessment or quantitative (HIMRISS)) and demographic parameters (age, sex, and BMI).
Predictive factors for response to HA injection: Clinical
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WOMAC pain, function and total score at baseline were not associated with WOMAC50 response, nor were any other baseline clinical parameters (table 2). MRI Femoral BML (binary assessment), HIMRISS BML femoral, HIMRISS BML acetabular and
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HIMRISS total, were negatively associated with the WOMAC50 response in the univariate analysis. HIMRISS synovitis-effusion tended to be negatively associated to WOMAC50
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response (table 2). Concerning the two patients dropped from the study for total hip
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replacement, one had low HIMRISS total value (16.3) while the second one presented moderate HIMRISS total value (37.6).
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In the multivariate analysis, adjusted for age and BMI, this association was only present for HIMRISS BML femoral (p=0.02) and HIMRISS total (p=0.016). In other words, patients with
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responder.
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low HIMRISS BML femoral and low HIMRISS total score have a better chance of being a
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A ROC curve was created with HIMRISS total score as the test variable and HA response as the categorical state variable. Using a threshold of baseline HIMRISS less than 15 (first quintile) the percentage of WOMAC50 responders is 82% (figure 2). Based on this ROC curve, the specificity for WOMAC50 response is 0.97 [0.90;1.00], and the sensitivity is 0.36 [0.16;0.56]. Only a quarter of patients were considered WOMAC50 responders for the highest quintile (greatest amount of BML at baseline).
MRI characteristics for injected versus non-injected hip: On the contralateral (non-injected) hip, patients with bilateral hip OA had a mean HIMRISS total of 21.1 [±17.0], and those with unilateral hip OA had a mean HIMRISS score of 11.3 [±7.7].
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All injected hips had joint synovitis-effusion and most (73.3%) had BML in the femoral head. In the contralateral (non-injected) hip, we noted a high prevalence of synovitis-effusion (89.3%), and a much lower prevalence of BML in the femoral head (35.7%). Overall, 100% of injected hips and 100% of contralateral hips in this population presented an active lesion
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(synovitis-effusion and/or BML) at baseline. Each HIMRISS domain and HIMRISS total of the injected hips were significantly higher at baseline than in non-injected hips, with higher
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scores for BML (mean total BML score 18.6 vs. 6.9) and effusion (score 13.9 vs. 7.8) (Table
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3).
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Discussion
This prospective multicenter study demonstrates the ability of HIMRISS semiquantitative
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analysis of active lesions in non-augmented MRI to predict the response to a specific
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patients.
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hyaluronic acid with mannitol (HAnox-M-XL) injection in a sample of symptomatic hip OA
As per OARSI recommendations (25), MRI was performed using multi-planar T1 and T2weighted sequences without contrast agent injection. We used HIMRISS assessment because it was previously validated, highly reliable between readers, and easy to perform with just one plane of acquisition (coronal). HIMRISS assessment of active lesions in hip OA, such as BML and synovitis-effusion, requires only coronal images. For HOAMS, BML and synovitiseffusion assessment require three planes of acquisition (coronal, sagittal, axial). In SHOMRI, only two planes (coronal and sagittal) are necessary. In this large multicenter study, MRI protocol acquisition allowed us to record HIMRISS scores for 92.3% MRI of injected hips, and 86.1% of both hips.
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We confirm the good to excellent inter-reader reliability for all MRI features scored by HIMRISS, without differences between rheumatologists and radiologist, and between senior and junior readers. The ICC for HIMRISS BML was 0.83 for femoral and 0.64 for acetabular, comparable to previous published values ranging from 0.55 to 0.94 for BML (11,13,18). For
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synovitis-effusion, ICC for HIMRISS is 0.78 and 0.55 for SHOMRI (8). Unlike HOAMS, HIMRISS does not differentiate synovitis from effusion, and both components are scored
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together. In HOAMS, ICC for synovitis and effusion are 0.60 and 0.65 respectively (18).
Concerning hip injected, we observed a high prevalence of inflammatory lesions for both
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synovitis-effusion and BML (respectively 100% and 81.6%). These results were also mentioned by Roemer and al (18), which found a relative comparable prevalence of
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inflammatory lesions by HOAMS, in a population of symptomatic and radiographic hip OA (synovitis, effusion and BML: 75%, 36.5% and 67.3% respectively.). In Lee and al study (11),
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the prevalence of synovitis-effusion and BML are much lower, 12.2% and 18.4%
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respectively, in a population where 77% of the patients do not have radiographic hip OA or considered as doubtful. The prevalence of inflammatory lesions should be interpreted with caution as it depends on the stage of OA, and population-based studies are lacking.
Correlation between MRI features and clinical symptoms are usually fair in osteoarthritis studies. In this study there was no association between baseline BML and clinical outcomes. Such an association was found in 5 previous studies and not seen in 2 others (10,11,13,16,18,27,28). The lack of association is probably related to the sample of patients composed of painful hip OA in escape for a standardized medical care with severe structural damages. However, we show a correlation between HIMRISS synovitis-effusion and WOMAC-Function at baseline. This association may be explained by the fact that a large
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effusion could limit joint motion and worsen disability. This result should be taken with caution, because it is the only clinical factor associated significantly with MRI features at baseline. Similarly though, Roemer and al (14) also found a trend toward association between
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HOAMS synovitis and Hip disability and osteoarthritis outcome score -function (HOOS).
None of the studied baseline clinical parameters permitted identification of responders for
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HA. Only HIMRISS BML (femoral and total) predicted a good response to treatment.
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Subjects with a HIMRISS score of less than 15 showed a high response to treatment (82%), dropping to 25% for subjects with the highest quintile of HIMRISS score. This study
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suggests that HA injection may be more effective in those patients with lower active lesions and is much less likely in those with extensive involvement with BML. Until now, these
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findings were only suggested by radiographic assessment (29–35).
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As for pelvic radiograph where structural damages were assessed on both hips, the use of
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coronal MRI allowed us to explore inflammatory lesions on both hips (injected and noninjected hips). So we showed for the first time that the targeted hip for injection was more symptomatic clinically than the contralateral hip, and presented on MRI, more inflammatory lesions as well as on binary and quantitative assessments. Even where HIMRISS score was lower in the contralateral hip, we noted a large number of patients with active lesions, as expected given the frequent bilateral nature of hip OA. This was particularly true for synovitis-effusion, while the frequency of femoral BML was lower in contralateral noninjected hips (89.3% versus 35.7%).
A strength of this study is the large sample of symptomatic patients included from many centers, avoiding local biases of inclusion and image acquisition. MRI features were assessed
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by four readers from different institutions, and read both by binary and semi-quantitative approaches (HIMRISS). Concerning the clinical outcomes and the percentage of patients considered as responders for WOMAC50 (45.5%), the results are quite similar to those previously published (29,36,37). This study has also some limits. There is no assessment of
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MRI structural lesions in hip OA (osteophytes, cartilage, labral tears, dysplasia, loose
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bodies…). The study was an observational open trial without a placebo group.
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In conclusion, we demonstrated that HIMRISS is a method that achieves high reliability for active lesions between readers despite minimal calibration, in a large multicenter trial.
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HIMRISS was able to differentiate differences in MRI inflammatory lesions between injected and non-injected hip OA. This approach was also able to identify that a relative lack of
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expected response to HA injection.
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baseline BML predicts response to HA injection in hip OA, and to propose a threshold for
Acknowledgements: GRRIF (Groupe de Recherche en Rhumatologie Interventionnel Français) and LABRHA (LABoratoire de RHumatologie Appliquée) for its participation as promotor and sponsor
Conflict of interest statement:
D.Loeuille declares no conflict of interest. N.Deseyne declares no conflict of interest. T.Conrozier declares to be a consultant for Labrha SAS, Sanofi and Aptissen, and a board membership of Genevrier. H.Lellouche declares to be a board membership of Genevrier and Sanofi. B.Maillet declares no conflict of interest. U. Weber declares no conflict of interest.
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J. Jaremko declares no conflict of interest. J.Paschke declares no conflict of interest. J.Epstein declares no conflict of interest. W.P.Maksymowych declares no conflict of interest.
Funding Statement
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All hyaluronic acid (HAnox-M-XL) were provided by LABRHA, for this study. The GRRIF, a section from the French Society of Rheumatology, which members are
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T.Conrozier, B.Maillet and H.Lellouche, conducted the study design, collection, and analysis
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of data. The collection and analysis of data were also made by W.Maksymowych, N.Deseyne and D.Loeuille.
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D.Loeuille, N.Deseyne, J.Jaremko, U.Weber made independently the lecture of MRI. The writing of the manuscript was done by D.Loeuille and N.Deseyne.
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The analysis of the data was made by J.Paschke and J.Epstein.
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16. Taljanovic MS, Graham AR, Benjamin JB, Gmitro AF, Krupinski EA, Schwartz SA, et al. Bone marrow edema pattern in advanced hip osteoarthritis: quantitative assessment with magnetic resonance imaging and correlation with clinical examination, radiographic findings, and histopathology. Skeletal Radiol. 2008 ;37(5):423–31.
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17. Xu L, Hayashi D, Roemer FW, Felson DT, Guermazi A. Magnetic Resonance Imaging of Subchondral Bone Marrow Lesions in Association with Osteoarthritis. Semin Arthritis Rheum. 2012 ;42(2):105–18.
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18. Roemer FW, Hunter DJ, Winterstein A, Li L, Kim YJ, Cibere J, et al. Hip Osteoarthritis MRI Scoring System (HOAMS): reliability and associations with radiographic and clinical findings. Osteoarthr Cartil. 2011 ;19(8):946–62.
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19. Kamimura M, Nakamura Y, Ikegami S, Mukaiyama K, Uchiyama S, Kato H. The Pathophysiology of Primary Hip Osteoarthritis may Originate from Bone Alterations. Open Rheumatol J. 2013 ;7:112–8. 20. Wang X, Blizzard L, Halliday A, Han W, Jin X, Cicuttini F, et al. Association between MRI-detected knee joint regional effusion-synovitis and structural changes in older adults: a cohort study. Ann Rheum Dis. 2016 ;75(3):519–25. 21. Eymard F, Maillet B, Lellouche H, Mellac-Ducamp S, Brocq O, Loeuille D, et al. Predictors of response to viscosupplementation in patients with hip osteoarthritis: results of a prospective, observational, multicentre, open-label, pilot study. BMC Musculoskelet Disord. 2017 ;18(1):3. 22. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988 ;15(12):1833–40. 23. Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, et al. OMERACT-OARSI Initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis and Cartilage. 2004 ;12(5):389–99.
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24. Conrozier T, Mathieu P, Rinaudo M. Mannitol Preserves the Viscoelastic Properties of Hyaluronic Acid in an In Vitro Model of Oxidative Stress. Rheumatol Ther. 2014 ;1(1):45–54. 25. Gold GE, Cicuttini F, Crema MD, Eckstein F, Guermazi A, Kijowski R, et al. OARSI Clinical Trials Recommendations: Hip imaging in clinical trials in osteoarthritis. Osteoarthr Cartil. 2015 ;23(5):716–31.
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26. Jaremko JL, Pitts M, Maksymowych WP, Lambert RG. Development of Image Overlay and Knowledge Transfer Module Technologies Aimed at Enhancing Feasibility and External Validation of Magnetic Resonance Imaging-based Scoring Systems. J Rheumatol. 2016 ;43(1):223–31.
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27. Jaremko JL, Lambert RGW, Zubler V, Weber U, Loeuille D, Roemer FW, et al. Methodologies for semiquantitative evaluation of hip osteoarthritis by magnetic resonance imaging: approaches based on the whole organ and focused on active lesions. J Rheumatol. 2014 ;41(2):359–69.
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28. Ahedi H, Aitken D, Blizzard L, Cicuttini F, Jones G. A population-based study of the association between hip bone marrow lesions, high cartilage signal, and hip and knee pain. Clin Rheumatol. 2013 ;33(3):369–76.
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29. Rennesson-Rey B, Rat A-C, Chary-Valckenaere I, Bettembourg-Brault I, Juge N, Dintinger H, et al. Does joint effusion influence the clinical response to a single Hylan GF-20 injection for hip osteoarthritis? Joint Bone Spine. 2008 ;75(2):182–8.
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30. Abate M, Pelotti P, De Amicis D, Di Iorio A, Galletti S, Salini V. Viscosupplementation with hyaluronic acid in hip osteoarthritis (a review). Ups J Med Sci. 2008;113(3):261– 77. 31. Brocq O, Tran G, Breuil V, Grisot C, Flory P, Euller-Ziegler L. Hip osteoarthritis: shortterm efficacy and safety of viscosupplementation by hylan G-F 20. An open-label study in 22 patients. Joint Bone Spine. 2002 ;69(4):388–91. 32. Migliore A, Alberto M, Massafra U, Umberto M, Bizzi E, Emanuele B, et al. Intraarticular injection of hyaluronic acid (MW 1,500-2,000 kDa; HyalOne) in symptomatic osteoarthritis of the hip: a prospective cohort study. Arch Orthop Trauma Surg. 2011 ;131(12):1677–85. 33. Qvistgaard E, Christensen R, Torp-Pedersen S, Bliddal H. Intra-articular treatment of hip osteoarthritis: a randomized trial of hyaluronic acid, corticosteroid, and isotonic saline. Osteoarthr Cartil. 2006 ;14(2):163–70. 34. Migliore A, Tormenta S, Massafra U, Carloni E, Padalino C, Iannessi F, et al. Repeated ultrasound-guided intra-articular injections of 40 mg of Hyalgan may be useful in symptomatic relief of hip osteoarthritis. Osteoarthr Cartil. 2005 ;13(12):1126–7. 35. Conrozier T, Bertin P, Bailleul F, Mathieu P, Charlot J, Vignon E, et al. Clinical response to intra-articular injections of hylan G-F 20 in symptomatic hip osteoarthritis: the OMERACT-OARSI criteria applied to the results of a pilot study. Joint Bone Spine. 2006 ;73(6):705–9.
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36. Conrozier T, Couris CM, Mathieu P, Merle-Vincent F, Piperno M, Coury F, et al. Safety, efficacy and predictive factors of efficacy of a single intra-articular injection of non-animal-stabilized-hyaluronic-acid in the hip joint: results of a standardized followup of patients treated for hip osteoarthritis in daily practice. Arch Orthop Trauma Surg. 2009;129(6):843–8.
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an
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37. Richette P, Ravaud P, Conrozier T, Euller-Ziegler L, Mazières B, Maugars Y, et al. Effect of hyaluronic acid in symptomatic hip osteoarthritis: a multicenter, randomized, placebo-controlled trial. Arthritis Rheum. 2009 ;60(3):824–30.
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Figure 1: A. Example of BML on the right femoral head. B. This BML is located in sector “1” and is scored as “1”. C. Example of synovitis-effusion on the right hip: the red arrow annotates the maximal depth of fluid perpendicular to the long axis (yellow line) of the fluid
B
C
C
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A
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collection, 5 mm in extent (grade 2).
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Figure 2: WOMAC50 responders according to HIMRISS total scores
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Table 1: Patient’s characteristics at baseline and 3 months after HA injection Population (n=60) Age (years) mean (SD)
62.6 [±11.0] 29 (48.3%)
BMI (kg/m²) mean (SD)
26.5 [±4.3]
Symptom's duration (months) mean (SD)
28.4 [±40.5]
Symptomatic hip: n (%) unilateral
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Sex: n (%) men
37 (61.7%)
Current Medication n (%)
Pain Killers
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NSAIDs
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Kellgren and Lawrence n (%)
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WOMAC50 response n (%)
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WOMAC Total (0-100) mean (SD)
VAS-GH (0-100) mean (SD)
18 (30%)
Physiotherapy
5 (8.3%)
Baseline
49.2 [±16.1]
3 months
31.1 [±22.7]
Baseline
44.1 [±18.3]
3 months
29.2 [±22.3]
Baseline
46.1 [±15.4]
3 months
29.8 [±20.5]
Baseline
63.8 [±14.7]
3 months
44.1 [±25.3]
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WOMAC Function (0-100) mean (SD)
21 (35)%
DMOAD
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WOMAC Pain (0-100) mean (SD)
38 (63.3%)
25 (45.5%) Grade 1
5 (8.3%)
Grade 2
20 (33.3%)
Grade 3
19 (31.7%)
Grade 4
7 (11.7%)
VAS-GH: visual analogic scale of global health assessment
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Table 2: Predictive factors of WOMAC50 response (univariate analysis) WOMAC50 response
p
No (n=30)
Yes (n=25)
Age mean (SD)
60.8 [±11.4]
65.1 [±10.2]
Male:female, n
14:16
BMI mean (SD)
Clinical data
P=0.90
26.6 [±5.1]
26.1 [±3.4]
P=0.93
Disease duration (month) mean (SD)
39.4 [±52.4]
18.4 [±16.6]
P=0.32
Previous hip infiltration, yes:no, n
5:25
3:22
P=0.72
WOMAC Pain at baseline mean (SD)
51.0 [±19.1]
48.4 [±10.2]
P=0.46
WOMAC Function at baseline mean (SD)
47.6 [±20.4]
40.0 [±13.6]
P=0.14
WOMAC Total at baseline mean (SD)
48.8 [±17.4]
43.1 [±11.3]
P=0.20
26 (86.7%)
14 (56.0%)
P<0.05
27 (90.0%)
19 (76.0%)
P=0.27
30 (100%)
25 (100%)
15.7 [±15.6]
6.7 [±8.8]
P<0.01
BML acetabular (0-35)
9.1 [±5.4]
6.0 [±5.2]
P<0.05
Effusion-synovitis (0-30)
15.5 [±6.7]
12.0 [±6.2]
P=0.062
Total (0-130)
40.8 [±23.3]
25.2 [±16.7]
P<0.01
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MRI data
BML acetabular Effusion-synovitis
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Binary MRI assessment: n (%) BML femoral
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13:12
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P=0.20
d
HIMRISS score: mean (SD)
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BML femoral (0-65)
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injected hip
non injected hip
(n= 60)
(n=56)
BML femoral
44 (73.3%)
20 (35.7%)
P<0.001
BML acetabular
49 (81.6%)
35 (62.5%)
P<0.05
Effusion-synovitis
60 (100%)
50 (89.3%)
P<0.05
Total
60 (100%)
56 (100%)
11.1 [±13.2]
2.9 [±5.9]
P<0.001
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Table 3: MRI features and HIMRISS in injected versus non-injected hips p
4.0 [±4.1]
P<0.001
7.8 [±5.7]
P<0.001
15.2 [±13.0]
P<0.001
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Binary MRI assessment, if present: n (%)
BML femoral (0-65)
7.5 [±5.5]
Effusion-synovitis (0-30)
13.9 [±6.8]
Total (0-130)
32.9 [±21.3]
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BML acetabular (0-35)
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HIMRISS score: mean (SD)
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S1297-319X(17)30158-6 http://dx.doi.org/doi:10.1016/j.jbspin.2017.08.004 BONSOI 4627
To appear in: Received date: Accepted date:
28-6-2017 31-8-2017
Please cite this article as: Deseyne N, Conrozier T, Lellouche H, Maillet B, Weber U, Jaremko JL, Paschke J, Epstein J, Maksymowych WP, Loeuille D, Hip Inflammation MRI Scoring System (HIMRISS) to predict response to hyaluronic acid injection in hip osteoarthritis, Joint Bone Spine (2017), http://dx.doi.org/10.1016/j.jbspin.2017.08.004 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Hip Inflammation MRI Scoring System (HIMRISS) to predict response to hyaluronic acid injection in hip osteoarthritis.
Jacob L. Jaremko f, Joel Paschkeg, Jonathan Epstein
h,
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Nicolas Deseynea, Thierry Conrozier b, Henri Lellouche c, Bernard Maillet d, Ulrich Weber e, Walter P. Maksymowych I, Damien
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Loeuille a
us
a - Department of Rheumatology, CHRU de Nancy, 54500 Vandoeuvre les Nancy, France
b - Department of Rheumatology, North Hospital Franche-Comté, 25200 Montbéliard, France
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c - Department of Rheumatology, Lariboisière Hospital, 75475 Paris cedex 10, France d - Department of Rheumatology, Clinique Saint Odilon, 03000 Moulins, France
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e - King Christian 10th Hospital for Rheumatic Diseases, Gråsten, Denmark, and Institute of Regional Health Research, University of Southern Denmark, 5000 Odense, Denmark
d
f - Dept. of Radiology and Diagnostic Imaging, University of Alberta, Edmonton, AB T6G 2R3, Canada
Canada
Ac ce pt e
g - CaRE Arthritis, Edmonton, Alberta T6W 2Z8, Canada.
h - CEC-Inserm CIE6, Epidemiology and Clinical Evaluations Department, CHRU Nancy, 54500 Vandoeuvre les Nancy, France
i - Department of Medicine, University of Alberta, Edmonton, Edmonton, Alberta, AB T6G 2R3, Canada.
Corresponding Author: Dr Nicolas Deseyne, [email protected] Service de Rhumatologie, CHRU Nancy, 5 Rue du Morvan, 54500 Vandœuvre-lès-Nancy
Abstract
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Objective: To assess predictors of response, according to hip MRI inflammatory scoring system (HIMRISS), in a sample of patients with hip osteoarthritis (OA) treated by hyaluronic acid (HA) injection. Method: 60 patients with hip OA were included. Clinical outcomes were assessed at baseline
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and three months after HA injection by WOMAC. On hip MRI performed before HA injection, bone marrow lesion (BML) and synovitis were assessed by HIMRISS by four
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readers. The inter-reader reliability of HIMRISS was for HIMRISS total, acetabular BML,
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femoral BML and synovitis-effusion respectively 0.86, 0.64, 0.83 and 0.78. Associations between MRI features and clinical data were assessed. Logistic regression (univariate and
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multivariate) was used to explore associations between MRI features and response to HA injection, according to WOMAC50 response at three months.
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Results: 45.5% of patients met WOMAC50 response. Five adverse events were reported. At baseline, WOMAC-function correlated significantly to HIMRISS synovitis-effusion (r=0.27,
d
p=0.03). In univariate analysis, BML femoral according to binary assessment (p=0.025),
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HIMRISS BML femoral (p=0.0038), HIMRISS BML acetabular (p=0.042), HIMRISS total (p=0.0092) were associated negatively with WOMAC50 response. In multivariate analysis, adjusted for age and BMI, HIMRISS femoral BML (p=0.02) and HIMRISS total (p=0.016) were negatively associated with response. At a HIMRISS threshold of <15, 82% of patients were responders, with specificity SP=0.97, sensitivity SN=0.39, and positive and negative predictive values of 0.91 and 0.64 respectively. Conclusion: HIMRISS is reliable for total scores and sub-domains. It permits identification of responders to HA injection in hip OA patients. Key Words : Osteoarthritis, hip, magnetic resonance imaging (MRI), bone marrow lesion, synovitis, HIMRISS, hyaluronate acid.
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ip t cr us an M d Ac ce pt e Introduction
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Osteoarthritis (OA) of the hip is common and potentially debilitating, with a prevalence of 3– 9 % in Western populations (1,2). It is the major reason for approximately 200,000 total hip replacements performed annually in the United States (3), and contributes significantly to the $185 billion estimated annual cost of OA (4). Hip OA was also shown to be associated with
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an increased risk of all-cause and cardiovascular mortality among older white women (5). The American College of Rheumatology (ACR) and Osteoarthritis Research Society International
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(OARSI) have defined clinical and radiographic criteria to standardize diagnosis and
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radiographic grading of hip OA (6,7). Magnetic resonance imaging (MRI) is more sensitive to early subtle tissue abnormalities (8) but its place remains limited in clinical practice (9).
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Recently, MRI scoring systems have been developed and validated which adopt a semi quantitative approach to assess various active and structural abnormalities in hip OA (10–15).
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Among all MRI features in OA, bone marrow lesion (BML) and synovitis show highest
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association (16–20).
d
correlations to hip pain (10). Concerning joint damage progression, only BML showed an
Concerning treatment response, only one study has compared the performance of HIMRISS and Hip Osteoarthritis MRI Scoring System (HOAMS) to evaluate the efficacy of intraarticular glucocorticoid injection on BML and synovitis in hip OA patients (10). Both scores demonstrated association between pain and MRI activity features at baseline, but the decrease of BML score was not correlated with pain improvement at week 12 for either system, whether decrease of synovitis was observed and was correlated with pain improvement.
Three scores, HOAMS, Scoring Hip Osteoarthritis with MRI (SHOMRI) and HIMRISS, assess BML and synovitis-effusion with excellent and good intra- and inter-reader reliabilities, respectively (10,11,18). For our study, HIMRISS was favoured because unlike
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HOAMS it did not require intravenous contrast injection, and SHOMRI was not published in full text before the beginning of this study. The primary objective of this study was to determine the MRI features predictive of response to viscosupplementation injection in a population of 60 patients with hip OA. The secondary goals were to determine the
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relationship between MRI features and hip symptoms, and to compare MRI lesion patterns
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and severity between injected versus non-injected hips.
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Patients and methods
The PREVICOX study is a prospective multicenter (40 study centers) (21) study, which aims
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to assess predictive factors (clinical and imaging) of response after intra-articular hyaluronate
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(HA) injection in patients with hip OA. The study was conducted in France, from November
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2013 to March 2015. This study was recorded at EudraCT, number 2013-A00165-40 in respect to the principles of Good Clinical Practice (GCP), and the Declaration of Helsinki concerning medical research in humans and the country-specific regulations. Before enrollment, patients were required to sign an informed consent form. The consent form and protocol, which complied with the requirements of the International Conference on Harmonization (ICH), were reviewed and approved by a French committee of ethic (Comité consultatif sur le traitement de l'information en matière de recherche scientifique (CCTIRS)). It was registered 31 January 2013 under the N° ID RCB 2013-A00165-40.
The inclusion criteria were:
Symptomatic Hip OA meeting ACR criteria (6), inadequate
response to NSAIDs or oral analgesic therapy. All patients had pelvic MRI examination performed before hip injection. Exclusion criteria were: allergy or known hypersensitivity to
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HA or mannitol, contraindication to hip injection, total hip replacement scheduled in the next three months, intra articular injection of corticosteroid the past month or injection of HA the past three months in targeted hip, patients with systematic or regional musculo-skeletal conditions (Rheumatoid Arthritis, Spondylarthritis, Lupus, Psoriasic arthritis, Paget’s disease,
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gout, sciatalgia), clinically relevant comorbidities (advanced and/or unstable cardiovascular pulmonary, neurological, haematology and endocrinopathy disorders, diabetes), and
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pregnancy.
Data collected at inclusion comprised: age, sex, height, weight, unilateral or bilateral hip
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osteoarthritis, the side of the symptomatic hip, symptom duration, type and quantity of oral medications used for hip OA (e.g. pain killer, NSAID, disease modifying anti osteoarthritic
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drug (DMOAD)), use of physiotherapy, previous corticosteroid and/or acid hyaluronic
contralateral and targeted hip.
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injection in the hip, surgical history: contralateral hip replacement, arthroscopy of
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Pain, stiffness and function were assessed by the Western Ontario & McMaster (WOMAC) questionnaire (22) (pain, stiffness, function) and global health assessment on a visual analogic scale (VAS) at inclusion and 12 weeks after intra-articular hyaluronate injection. Adverse events (AEs) were collected at each visit and categorized using the Medical Dictionary for Regulatory Activities (MedDRA). Definition of adverse events (AEs) and serious adverse events (SAEs) were in accordance with the European standard EN ISO 14155: 2011. Investigators had to note all AEs on the report form.
The response to the HA injection was defined by a high improvement on OARSI-OMERACT criteria (23). Responders presented an improvement of WOMAC Pain and/or WOMAC Function> 50% with an absolute value of change >20 UI.
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Hip injection was performed according to fluoroscopic or ultrasonographic procedures with HAnox-M-XL
(marketed
as
HAppyCross®,
LABRHA
SAS,
Lyon,
France),
a
viscosupplement that combines a high molecular weight, cross-linked sodium hyaluronate of
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non-animal origin (16 g/l) with mannitol (35 g/l) (oxygen free radicals neutralization (24)),
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supplied in a ready-to-use 2.2 ml syringe.
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MRI protocol:
All 60 patients had coronal T1 and T2 sequences. 56 patients had a pelvic MRI, and 4 patients
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only unilateral hip MRI assessment. In total, all patients had at least two planes of acquisition in MRI, and 27 (45%) had three-dimensional examination.
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All patients received a coronal fluid-sensitive MRI sequence: 26 patients had STIR sequences, 34 T2-FS (fat saturated), with slice thickness (3-5.5 mm), matrix size (256x256-456x402),
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and a wide FOV limited to the pelvic region. This MRI protocol satisfied OARSI
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recommendations (25). All MRI were scored by four readers including three rheumatologists (two seniors (DL, UW), one junior (ND)) and one senior radiologist (JJ), blinded to clinical information.
MRI assessment:
-Firstly a binary assessment was performed on synovitis-effusion, BML femoral and acetabular, and a lesion was noted as present or absent if at least two of the three seniors readers agreed. -Secondly a semi-quantitative approach was performed, according to the HIMRISS method. Reading was performed by the four readers after a minimal calibration on an e-learning module, and hips were scored on a web-based overlay integrated with a web-based DICOM
Page 7 of 24
viewer designed for use with DICOM MR images of the hip (26). By dragging with a mouse the overlay was positioned over the largest diameter of the femoral head and resized to ensure alignment with the subchondral bone. On pelvic MRI, both hips were scored, blindly to the targeted hip.
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The HIMRISS method was applied according to the following manner (27): presence or absence of BML in each of the sectors is scored dichotomously directly on the image display.
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The central 5 slices (centered on the “central slice”) show most of the head volume (figure 1
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Legend of the figure 1: A. Example of BML on the right femoral head (white arrow). B. This BML is located in sector “1” and is scored as “1” (white arrow). C. Example of synovitis-
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effusion on the right hip: the black arrow annotates the maximal depth of fluid perpendicular to the long axis (white line) of the fluid collection, 5 mm in extent (grade 2). ). In each of
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these slices, 9 sectors are defined, 8 around a clock face (starting superomedially) and the last central. For up to 5 remaining anterior slices containing femoral head, pair of regions
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(anterior-superior, anterior-inferior) is formed. This is also done for up to 5 posterior slices.
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Thus the femoral BML score varied from 0 to 65 points. BML of the acetabulum is assessed in the central 5 slices as described above, the acetabulum is divided into 3 regions containing a similar volume of sub - articular bone. In up to 5 slices anterior to the central slices, acetabulum is scored in 2 regions each (superior and inferior), and this is repeated for up to 5 slices posterior to central slices. The acetabular BML score ranged from 0 to 35 points. Total BML score varied from 0 to 100.
Synovitis and effusion score are scored in 2 locations according to a grading scheme (0-2) that reflects thickness of synovitis-effusion (Grade 0: < 2 mm, grade 1: 2–4 mm, grade 2:> 4 mm). The maximum combined thickness of synovium and fluid contacting the femur, perpendicular to the bone, was measured and this was repeated in each of the same 15 slices used for
Page 8 of 24
acetabular scoring (figure 1). The effusion-synovitis score ranged from 0 to 30. Finally, the total HIMRISS score is ranged from 0 to 130.
To establish the mean HIMRISS score of each patient, the scores of the three senior readers
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(with at least ten years of imaging experience in musculo-skeletal diseases) and the junior reader were used. Inter reader reliability (n=4) for HIMRISS was excellent for BML femoral
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and total score, with ICC [95% CI], 0.83[0.78-0.87] and 0.86 [0.81-0.89], and good for
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acetabular BML and synovitis-effusion, at 0.64 [0.52-0.74] and 0.78 [0.65-0.86] respectively.
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There was no difference between the three senior readers and the junior reader.
Statistical analysis
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A descriptive analysis was performed for clinical and imaging data. Qualitative variables were
using mean and standard deviation.
d
described using absolute numbers and percentages. Quantitative variables were described
Ac ce pt e
Differences regarding injected versus non-injected hip on MRI, and predictive factors of response were analyzed using univariate and/or multivariate comparison (CHI² or Fischer’s exact test, Mann and Whitney test) regarding clinical characteristics and MRI features of the patients. HIMRISS score was used as an outcome in linear regression with a stepwise model. P<0.05 was considered statistically significant. The statistical analysis was carried out using SAS® version 9.1 (SAS Institute Inc., Cary, NC).
Results At baseline, 60 MRI were available for HIMRISS assessment, and 55 patients completed the follow-up examination (2 patients dropped from the study for joint hip replacement, and 3 patients for withdrawn).
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As shown in Table 1, patients presented severe disability (mean WOMAC function: 44.1/100) and severe painful hip OA (mean WOMAC pain: 49.2/100) with unilateral hip OA in 61.7% of the cases (n=37). On these 60 patients, 8.3% were classified Kellgren and Lawrence grade 1, 33.3% grade 2,
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31.7% grade 3 and 11.7% grade 4. 23 patients were known as presented a bilateral hip OA
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(38.3%) on the clinical evaluation.
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For WOMAC50 (pain and/or function), 45.5% were responders at three months to HA injection. Five adverse events were reported (8.3%). Two were classified as device/procedure
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AEs (3.3%). All 2 were described as an increase of the hip pain that occurred the very next hours after injection. One resolved in less than 24 hours with rest and paracetamol. One
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resolved in 1 week and needed NSAIDs. The other AES were low back pain (1 case), knee pain in patient with knee OA (1 case) and dizziness (1 case) and were considered as unrelated
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to the treatment and/or the procedure of injection.
Correlation between MRI features and patients’ symptoms at baseline: No association was found between MRI activity features and patient symptoms, except for a fair correlation (ICC 0.27) between HIMRISS synovitis-effusion and WOMAC-function at baseline (p=0.03).
There was no association between MRI features (binary assessment or quantitative (HIMRISS)) and demographic parameters (age, sex, and BMI).
Predictive factors for response to HA injection: Clinical
Page 10 of 24
WOMAC pain, function and total score at baseline were not associated with WOMAC50 response, nor were any other baseline clinical parameters (table 2). MRI Femoral BML (binary assessment), HIMRISS BML femoral, HIMRISS BML acetabular and
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HIMRISS total, were negatively associated with the WOMAC50 response in the univariate analysis. HIMRISS synovitis-effusion tended to be negatively associated to WOMAC50
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response (table 2). Concerning the two patients dropped from the study for total hip
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replacement, one had low HIMRISS total value (16.3) while the second one presented moderate HIMRISS total value (37.6).
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In the multivariate analysis, adjusted for age and BMI, this association was only present for HIMRISS BML femoral (p=0.02) and HIMRISS total (p=0.016). In other words, patients with
d
responder.
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low HIMRISS BML femoral and low HIMRISS total score have a better chance of being a
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A ROC curve was created with HIMRISS total score as the test variable and HA response as the categorical state variable. Using a threshold of baseline HIMRISS less than 15 (first quintile) the percentage of WOMAC50 responders is 82% (figure 2). Based on this ROC curve, the specificity for WOMAC50 response is 0.97 [0.90;1.00], and the sensitivity is 0.36 [0.16;0.56]. Only a quarter of patients were considered WOMAC50 responders for the highest quintile (greatest amount of BML at baseline).
MRI characteristics for injected versus non-injected hip: On the contralateral (non-injected) hip, patients with bilateral hip OA had a mean HIMRISS total of 21.1 [±17.0], and those with unilateral hip OA had a mean HIMRISS score of 11.3 [±7.7].
Page 11 of 24
All injected hips had joint synovitis-effusion and most (73.3%) had BML in the femoral head. In the contralateral (non-injected) hip, we noted a high prevalence of synovitis-effusion (89.3%), and a much lower prevalence of BML in the femoral head (35.7%). Overall, 100% of injected hips and 100% of contralateral hips in this population presented an active lesion
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(synovitis-effusion and/or BML) at baseline. Each HIMRISS domain and HIMRISS total of the injected hips were significantly higher at baseline than in non-injected hips, with higher
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scores for BML (mean total BML score 18.6 vs. 6.9) and effusion (score 13.9 vs. 7.8) (Table
us
3).
an
Discussion
This prospective multicenter study demonstrates the ability of HIMRISS semiquantitative
M
analysis of active lesions in non-augmented MRI to predict the response to a specific
Ac ce pt e
patients.
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hyaluronic acid with mannitol (HAnox-M-XL) injection in a sample of symptomatic hip OA
As per OARSI recommendations (25), MRI was performed using multi-planar T1 and T2weighted sequences without contrast agent injection. We used HIMRISS assessment because it was previously validated, highly reliable between readers, and easy to perform with just one plane of acquisition (coronal). HIMRISS assessment of active lesions in hip OA, such as BML and synovitis-effusion, requires only coronal images. For HOAMS, BML and synovitiseffusion assessment require three planes of acquisition (coronal, sagittal, axial). In SHOMRI, only two planes (coronal and sagittal) are necessary. In this large multicenter study, MRI protocol acquisition allowed us to record HIMRISS scores for 92.3% MRI of injected hips, and 86.1% of both hips.
Page 12 of 24
We confirm the good to excellent inter-reader reliability for all MRI features scored by HIMRISS, without differences between rheumatologists and radiologist, and between senior and junior readers. The ICC for HIMRISS BML was 0.83 for femoral and 0.64 for acetabular, comparable to previous published values ranging from 0.55 to 0.94 for BML (11,13,18). For
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synovitis-effusion, ICC for HIMRISS is 0.78 and 0.55 for SHOMRI (8). Unlike HOAMS, HIMRISS does not differentiate synovitis from effusion, and both components are scored
us
cr
together. In HOAMS, ICC for synovitis and effusion are 0.60 and 0.65 respectively (18).
Concerning hip injected, we observed a high prevalence of inflammatory lesions for both
an
synovitis-effusion and BML (respectively 100% and 81.6%). These results were also mentioned by Roemer and al (18), which found a relative comparable prevalence of
M
inflammatory lesions by HOAMS, in a population of symptomatic and radiographic hip OA (synovitis, effusion and BML: 75%, 36.5% and 67.3% respectively.). In Lee and al study (11),
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the prevalence of synovitis-effusion and BML are much lower, 12.2% and 18.4%
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respectively, in a population where 77% of the patients do not have radiographic hip OA or considered as doubtful. The prevalence of inflammatory lesions should be interpreted with caution as it depends on the stage of OA, and population-based studies are lacking.
Correlation between MRI features and clinical symptoms are usually fair in osteoarthritis studies. In this study there was no association between baseline BML and clinical outcomes. Such an association was found in 5 previous studies and not seen in 2 others (10,11,13,16,18,27,28). The lack of association is probably related to the sample of patients composed of painful hip OA in escape for a standardized medical care with severe structural damages. However, we show a correlation between HIMRISS synovitis-effusion and WOMAC-Function at baseline. This association may be explained by the fact that a large
Page 13 of 24
effusion could limit joint motion and worsen disability. This result should be taken with caution, because it is the only clinical factor associated significantly with MRI features at baseline. Similarly though, Roemer and al (14) also found a trend toward association between
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HOAMS synovitis and Hip disability and osteoarthritis outcome score -function (HOOS).
None of the studied baseline clinical parameters permitted identification of responders for
cr
HA. Only HIMRISS BML (femoral and total) predicted a good response to treatment.
us
Subjects with a HIMRISS score of less than 15 showed a high response to treatment (82%), dropping to 25% for subjects with the highest quintile of HIMRISS score. This study
an
suggests that HA injection may be more effective in those patients with lower active lesions and is much less likely in those with extensive involvement with BML. Until now, these
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findings were only suggested by radiographic assessment (29–35).
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As for pelvic radiograph where structural damages were assessed on both hips, the use of
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coronal MRI allowed us to explore inflammatory lesions on both hips (injected and noninjected hips). So we showed for the first time that the targeted hip for injection was more symptomatic clinically than the contralateral hip, and presented on MRI, more inflammatory lesions as well as on binary and quantitative assessments. Even where HIMRISS score was lower in the contralateral hip, we noted a large number of patients with active lesions, as expected given the frequent bilateral nature of hip OA. This was particularly true for synovitis-effusion, while the frequency of femoral BML was lower in contralateral noninjected hips (89.3% versus 35.7%).
A strength of this study is the large sample of symptomatic patients included from many centers, avoiding local biases of inclusion and image acquisition. MRI features were assessed
Page 14 of 24
by four readers from different institutions, and read both by binary and semi-quantitative approaches (HIMRISS). Concerning the clinical outcomes and the percentage of patients considered as responders for WOMAC50 (45.5%), the results are quite similar to those previously published (29,36,37). This study has also some limits. There is no assessment of
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MRI structural lesions in hip OA (osteophytes, cartilage, labral tears, dysplasia, loose
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bodies…). The study was an observational open trial without a placebo group.
us
In conclusion, we demonstrated that HIMRISS is a method that achieves high reliability for active lesions between readers despite minimal calibration, in a large multicenter trial.
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HIMRISS was able to differentiate differences in MRI inflammatory lesions between injected and non-injected hip OA. This approach was also able to identify that a relative lack of
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expected response to HA injection.
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baseline BML predicts response to HA injection in hip OA, and to propose a threshold for
Acknowledgements: GRRIF (Groupe de Recherche en Rhumatologie Interventionnel Français) and LABRHA (LABoratoire de RHumatologie Appliquée) for its participation as promotor and sponsor
Conflict of interest statement:
D.Loeuille declares no conflict of interest. N.Deseyne declares no conflict of interest. T.Conrozier declares to be a consultant for Labrha SAS, Sanofi and Aptissen, and a board membership of Genevrier. H.Lellouche declares to be a board membership of Genevrier and Sanofi. B.Maillet declares no conflict of interest. U. Weber declares no conflict of interest.
Page 15 of 24
J. Jaremko declares no conflict of interest. J.Paschke declares no conflict of interest. J.Epstein declares no conflict of interest. W.P.Maksymowych declares no conflict of interest.
Funding Statement
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All hyaluronic acid (HAnox-M-XL) were provided by LABRHA, for this study. The GRRIF, a section from the French Society of Rheumatology, which members are
cr
T.Conrozier, B.Maillet and H.Lellouche, conducted the study design, collection, and analysis
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of data. The collection and analysis of data were also made by W.Maksymowych, N.Deseyne and D.Loeuille.
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D.Loeuille, N.Deseyne, J.Jaremko, U.Weber made independently the lecture of MRI. The writing of the manuscript was done by D.Loeuille and N.Deseyne.
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The analysis of the data was made by J.Paschke and J.Epstein.
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13. Kumar D, Wyatt CR, Lee S, Nardo L, Link TM, Majumdar S, et al. Association of Cartilage Defects, and other MR Findings with Pain and Function in Individuals with Mild-Moderate Radiographic Hip Osteoarthritis and Controls. Osteoarthritis Cartilage. 2013 ;21(11):1685–92. 14. Teichtahl AJ, Wang Y, Smith S, Wluka AE, Giles GG, Bennell KL, et al. Structural changes of hip osteoarthritis using magnetic resonance imaging. Arthritis Res Ther. 2014;16(5):466.
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15. Jaremko JL, Azmat O, Lambert RG, Bird P, Haugen IK, Jans L, et al. Validation of a Knowledge Transfer Tool for the Knee Inflammation MRI Scoring System for Bone Marrow Lesions According to the OMERACT Filter: Data from the Osteoarthritis Initiative. J Rheumatol. 2017 . doi: 10.3899/jrheum.161101.
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16. Taljanovic MS, Graham AR, Benjamin JB, Gmitro AF, Krupinski EA, Schwartz SA, et al. Bone marrow edema pattern in advanced hip osteoarthritis: quantitative assessment with magnetic resonance imaging and correlation with clinical examination, radiographic findings, and histopathology. Skeletal Radiol. 2008 ;37(5):423–31.
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17. Xu L, Hayashi D, Roemer FW, Felson DT, Guermazi A. Magnetic Resonance Imaging of Subchondral Bone Marrow Lesions in Association with Osteoarthritis. Semin Arthritis Rheum. 2012 ;42(2):105–18.
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18. Roemer FW, Hunter DJ, Winterstein A, Li L, Kim YJ, Cibere J, et al. Hip Osteoarthritis MRI Scoring System (HOAMS): reliability and associations with radiographic and clinical findings. Osteoarthr Cartil. 2011 ;19(8):946–62.
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19. Kamimura M, Nakamura Y, Ikegami S, Mukaiyama K, Uchiyama S, Kato H. The Pathophysiology of Primary Hip Osteoarthritis may Originate from Bone Alterations. Open Rheumatol J. 2013 ;7:112–8. 20. Wang X, Blizzard L, Halliday A, Han W, Jin X, Cicuttini F, et al. Association between MRI-detected knee joint regional effusion-synovitis and structural changes in older adults: a cohort study. Ann Rheum Dis. 2016 ;75(3):519–25. 21. Eymard F, Maillet B, Lellouche H, Mellac-Ducamp S, Brocq O, Loeuille D, et al. Predictors of response to viscosupplementation in patients with hip osteoarthritis: results of a prospective, observational, multicentre, open-label, pilot study. BMC Musculoskelet Disord. 2017 ;18(1):3. 22. Bellamy N, Buchanan WW, Goldsmith CH, Campbell J, Stitt LW. Validation study of WOMAC: a health status instrument for measuring clinically important patient relevant outcomes to antirheumatic drug therapy in patients with osteoarthritis of the hip or knee. J Rheumatol. 1988 ;15(12):1833–40. 23. Pham T, van der Heijde D, Altman RD, Anderson JJ, Bellamy N, Hochberg M, et al. OMERACT-OARSI Initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis and Cartilage. 2004 ;12(5):389–99.
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24. Conrozier T, Mathieu P, Rinaudo M. Mannitol Preserves the Viscoelastic Properties of Hyaluronic Acid in an In Vitro Model of Oxidative Stress. Rheumatol Ther. 2014 ;1(1):45–54. 25. Gold GE, Cicuttini F, Crema MD, Eckstein F, Guermazi A, Kijowski R, et al. OARSI Clinical Trials Recommendations: Hip imaging in clinical trials in osteoarthritis. Osteoarthr Cartil. 2015 ;23(5):716–31.
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26. Jaremko JL, Pitts M, Maksymowych WP, Lambert RG. Development of Image Overlay and Knowledge Transfer Module Technologies Aimed at Enhancing Feasibility and External Validation of Magnetic Resonance Imaging-based Scoring Systems. J Rheumatol. 2016 ;43(1):223–31.
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27. Jaremko JL, Lambert RGW, Zubler V, Weber U, Loeuille D, Roemer FW, et al. Methodologies for semiquantitative evaluation of hip osteoarthritis by magnetic resonance imaging: approaches based on the whole organ and focused on active lesions. J Rheumatol. 2014 ;41(2):359–69.
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28. Ahedi H, Aitken D, Blizzard L, Cicuttini F, Jones G. A population-based study of the association between hip bone marrow lesions, high cartilage signal, and hip and knee pain. Clin Rheumatol. 2013 ;33(3):369–76.
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29. Rennesson-Rey B, Rat A-C, Chary-Valckenaere I, Bettembourg-Brault I, Juge N, Dintinger H, et al. Does joint effusion influence the clinical response to a single Hylan GF-20 injection for hip osteoarthritis? Joint Bone Spine. 2008 ;75(2):182–8.
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30. Abate M, Pelotti P, De Amicis D, Di Iorio A, Galletti S, Salini V. Viscosupplementation with hyaluronic acid in hip osteoarthritis (a review). Ups J Med Sci. 2008;113(3):261– 77. 31. Brocq O, Tran G, Breuil V, Grisot C, Flory P, Euller-Ziegler L. Hip osteoarthritis: shortterm efficacy and safety of viscosupplementation by hylan G-F 20. An open-label study in 22 patients. Joint Bone Spine. 2002 ;69(4):388–91. 32. Migliore A, Alberto M, Massafra U, Umberto M, Bizzi E, Emanuele B, et al. Intraarticular injection of hyaluronic acid (MW 1,500-2,000 kDa; HyalOne) in symptomatic osteoarthritis of the hip: a prospective cohort study. Arch Orthop Trauma Surg. 2011 ;131(12):1677–85. 33. Qvistgaard E, Christensen R, Torp-Pedersen S, Bliddal H. Intra-articular treatment of hip osteoarthritis: a randomized trial of hyaluronic acid, corticosteroid, and isotonic saline. Osteoarthr Cartil. 2006 ;14(2):163–70. 34. Migliore A, Tormenta S, Massafra U, Carloni E, Padalino C, Iannessi F, et al. Repeated ultrasound-guided intra-articular injections of 40 mg of Hyalgan may be useful in symptomatic relief of hip osteoarthritis. Osteoarthr Cartil. 2005 ;13(12):1126–7. 35. Conrozier T, Bertin P, Bailleul F, Mathieu P, Charlot J, Vignon E, et al. Clinical response to intra-articular injections of hylan G-F 20 in symptomatic hip osteoarthritis: the OMERACT-OARSI criteria applied to the results of a pilot study. Joint Bone Spine. 2006 ;73(6):705–9.
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36. Conrozier T, Couris CM, Mathieu P, Merle-Vincent F, Piperno M, Coury F, et al. Safety, efficacy and predictive factors of efficacy of a single intra-articular injection of non-animal-stabilized-hyaluronic-acid in the hip joint: results of a standardized followup of patients treated for hip osteoarthritis in daily practice. Arch Orthop Trauma Surg. 2009;129(6):843–8.
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37. Richette P, Ravaud P, Conrozier T, Euller-Ziegler L, Mazières B, Maugars Y, et al. Effect of hyaluronic acid in symptomatic hip osteoarthritis: a multicenter, randomized, placebo-controlled trial. Arthritis Rheum. 2009 ;60(3):824–30.
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Figure 1: A. Example of BML on the right femoral head. B. This BML is located in sector “1” and is scored as “1”. C. Example of synovitis-effusion on the right hip: the red arrow annotates the maximal depth of fluid perpendicular to the long axis (yellow line) of the fluid
B
C
C
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A
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collection, 5 mm in extent (grade 2).
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Figure 2: WOMAC50 responders according to HIMRISS total scores
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Table 1: Patient’s characteristics at baseline and 3 months after HA injection Population (n=60) Age (years) mean (SD)
62.6 [±11.0] 29 (48.3%)
BMI (kg/m²) mean (SD)
26.5 [±4.3]
Symptom's duration (months) mean (SD)
28.4 [±40.5]
Symptomatic hip: n (%) unilateral
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Sex: n (%) men
37 (61.7%)
Current Medication n (%)
Pain Killers
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NSAIDs
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Kellgren and Lawrence n (%)
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WOMAC50 response n (%)
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WOMAC Total (0-100) mean (SD)
VAS-GH (0-100) mean (SD)
18 (30%)
Physiotherapy
5 (8.3%)
Baseline
49.2 [±16.1]
3 months
31.1 [±22.7]
Baseline
44.1 [±18.3]
3 months
29.2 [±22.3]
Baseline
46.1 [±15.4]
3 months
29.8 [±20.5]
Baseline
63.8 [±14.7]
3 months
44.1 [±25.3]
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WOMAC Function (0-100) mean (SD)
21 (35)%
DMOAD
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WOMAC Pain (0-100) mean (SD)
38 (63.3%)
25 (45.5%) Grade 1
5 (8.3%)
Grade 2
20 (33.3%)
Grade 3
19 (31.7%)
Grade 4
7 (11.7%)
VAS-GH: visual analogic scale of global health assessment
Page 22 of 24
Table 2: Predictive factors of WOMAC50 response (univariate analysis) WOMAC50 response
p
No (n=30)
Yes (n=25)
Age mean (SD)
60.8 [±11.4]
65.1 [±10.2]
Male:female, n
14:16
BMI mean (SD)
Clinical data
P=0.90
26.6 [±5.1]
26.1 [±3.4]
P=0.93
Disease duration (month) mean (SD)
39.4 [±52.4]
18.4 [±16.6]
P=0.32
Previous hip infiltration, yes:no, n
5:25
3:22
P=0.72
WOMAC Pain at baseline mean (SD)
51.0 [±19.1]
48.4 [±10.2]
P=0.46
WOMAC Function at baseline mean (SD)
47.6 [±20.4]
40.0 [±13.6]
P=0.14
WOMAC Total at baseline mean (SD)
48.8 [±17.4]
43.1 [±11.3]
P=0.20
26 (86.7%)
14 (56.0%)
P<0.05
27 (90.0%)
19 (76.0%)
P=0.27
30 (100%)
25 (100%)
15.7 [±15.6]
6.7 [±8.8]
P<0.01
BML acetabular (0-35)
9.1 [±5.4]
6.0 [±5.2]
P<0.05
Effusion-synovitis (0-30)
15.5 [±6.7]
12.0 [±6.2]
P=0.062
Total (0-130)
40.8 [±23.3]
25.2 [±16.7]
P<0.01
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MRI data
BML acetabular Effusion-synovitis
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Binary MRI assessment: n (%) BML femoral
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13:12
an
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P=0.20
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HIMRISS score: mean (SD)
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BML femoral (0-65)
Page 23 of 24
injected hip
non injected hip
(n= 60)
(n=56)
BML femoral
44 (73.3%)
20 (35.7%)
P<0.001
BML acetabular
49 (81.6%)
35 (62.5%)
P<0.05
Effusion-synovitis
60 (100%)
50 (89.3%)
P<0.05
Total
60 (100%)
56 (100%)
11.1 [±13.2]
2.9 [±5.9]
P<0.001
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Table 3: MRI features and HIMRISS in injected versus non-injected hips p
4.0 [±4.1]
P<0.001
7.8 [±5.7]
P<0.001
15.2 [±13.0]
P<0.001
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Binary MRI assessment, if present: n (%)
BML femoral (0-65)
7.5 [±5.5]
Effusion-synovitis (0-30)
13.9 [±6.8]
Total (0-130)
32.9 [±21.3]
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BML acetabular (0-35)
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HIMRISS score: mean (SD)
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