The use of efficient treatment with a treat-to-target strategy combined with early detection of the disease completely changed the imaging presentation and outcome of newly diagnosed rheumatoid arthritis (RA) patients. Magnetic Resonance Imaging (MRI) has become the reference technique in clinical research to detect and quantify inflammatory involvement of the soft tissues (synovitis and tenosynovitis) and bone marrow (osteitis) along with structural damages of the bone (erosions) in hands of patients with RA. Three-point Dixon MRI may be a valuable alternative to the currently recommended sequences as it yields effective fat signal suppression, high imaging quality and reproducible assessment of disease activity.
The current article aims to depict the evolution of rheumatoid arthritis (RA) imaging in the last decades and the potential advantages of Dixon Magnetic Resonance Imaging (MRI) sequences in the quantitative assessment of early RA disease activity in hands with the Rheumatoid Arthritis MRI scoring system (RAMRIS).
RA is a chronic inflammatory disorder affecting multiple organ systems and the most common type of autoimmune arthritis. Between 0.5% and 1.0% of the population suffers from RA worldwide . The physiopathology of RA is complex resulting in synovial membrane inflammation with a predilection for small joints of hands and feet . There are no definitive diagnostic criteria for RA: the final diagnosis is based on the experience of the clinician and the collection of clinical, biological, and sometimes imaging findings. Histology and genetic are not part of the diagnosis of RA in clinical practice. In the absence of effective treatment, RA may result in joint destruction (structural damage) and associated disability. However, the availability of disease-modifying anti-rheumatic drugs (DMARDs), first Methotrexate in the early 1990s and then biological DMARDs in the late 1990s, have dramatically changed the clinical management of RA patients and their outcomes .
Structural joint damages i.e. bone erosions and cartilage loss reflect chronic active inflammatory involvement of the joint. Historically, plain radiography has been the primary imaging technique to detect, characterize and monitor structural damage in RA patients. Before effective treatment became available, structural damages were common in late RA and presence of bone erosions on radiographs of the hands and wrists was a criterion for the classification of the disease proposed by the American College of Radiology (ACR) in 1987 .
New classification criteria including specific autoantibodies (anti-citrullinated protein antibody – ACPA) were developed to improve the detection of early disease. The use of efficient treatment with a treat-to-target strategy combined with early detection of the disease completely changed the radiographical outcome of newly diagnosed RA patients [5, 6, 7]. Structural damage has become rare and radiographic changes are no longer part of the classification criteria for RA .
Ultrasonography and MRI emerged as key imaging techniques in the management of RA as both are able to assess early inflammatory involvement of the soft tissues i.e. synovitis and tenosynovitis (Figure 1) . Interestingly, MRI is able to assess bone inflammation i.e. osteitis which may serve as a prognostic factor in the outcome of RA [10, 11, 12, 13, 14]. In the latest classification criteria, actively diseased joints on ultrasound or MRI can be considered for the active joint count along with clinically active joints . Several studies demonstrated the usefulness of intravenous Gadolinium-based contrast material injection and dynamic analysis of enhancing synovitis on MRI to characterize and monitor the disease [15, 16, 17]. Contrast-enhanced MRI has been demonstrated more sensitive and specific than non-enhanced fat-suppressed T2-weighted imaging or diffusion-weighted imaging to assess disease activity [18, 19]. Accumulation of Gadolinium-based contrast agent in the body is now well established even if its potential toxicity remains uncertain [20, 21]. Thus, precautionary measures should encourage the use of alternative to gadolinium-based contrast-enhanced MRI.
Few studies investigated whole-body MRI to assess and monitor RA disease activity in peripheral and axial joints [22, 23]. Non-conventional imaging modalities such as 18-F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) and infrared thermography have also been investigated to assess disease activity in RA [24, 25, 26]. These imaging techniques do not take part in the management of RA in clinical practice.
Methods to quantify disease activity based on medical imaging have been proposed to monitor the disease in clinical practice and establish the efficacy of new treatment in clinical studies.
First several semi-quantitative scoring methods based on bone and cartilage loss on radiographs of the extremities were developed . Among them, the method described by Sharp, later modified by van der Heijde in 1989 still serves as a reference to assess structural damage . Semi-quantitative gradings have also been proposed to evaluate disease activity with grayscale and power Doppler ultrasound. The scoring at ultrasound still shows limited reliability [29, 30].
In 2003, Outcome Measures in Rheumatology (OMERACT), a multi-institution study group, developed a semi-quantitative scoring system to asses RA activity at MRI, the RAMRIS . RAMRIS first included the scoring of synovitis, osteitis, and erosions with addition of tenosynovitis and cartilage loss in 2016 [32, 33].
An ‘optional’ cartilage dedicated fat-suppressed 3D gradient echo sequence has been proposed to improve the assessment of cartilage . RAMRIS is currently the reference to score disease activity on MRI [35, 36, 37].
Fat suppression is essential in musculoskeletal MRI as it allows better detection of lesions with increased water content on T2-weighted images and better detection of enhancing tissue on T1-weighted images after intravenous gadolinium-based contrast-material injection. Several techniques are available to obtain fat suppression, and each has its advantages and limits (Table 1) .
|Mechanism||Intrinsic fat suppression due to its 180° inversion and 90° excitation pulses||Chemically selective radiofrequency pulse before the acquisition of the signal||Post-processing with addition and subtraction of ‘in-phase’ and ‘out-of-phase’ images|
|B0 sensitivity||Insensitive||Sensitive||Insensitive (three-and four-point Dixon)|
|Preferred Field Strength||Indifferent||High||Medium|
|Imaging type||Not used on T1-weighted images||T1, T2, PD SE, GE||T1, T2, PD SE, GE|
|Fat suppression effectiveness||+++||++||+++|
|Imaging time||Long||Short (depends on the pulse sequence)||Long|
|Specific artifacts||/||Fat suppression failure||Fat-water swapping|
|Other||/||/||Production of four images|
Short-Tau Inversion-Recovery (STIR) sequence is insensitive to B0- and B1- fields heterogeneity which therefore brings homogenous fat suppression. However, it is useless on T1-weighted images as it cancels both fat and enhancing tissue and its low signal-to-noise ratio (SNR) is a concern in the evaluation of complex and small anatomical structures as in wrists and hands .
The chemical-shift selective (CHESS) technique is based on the frequency-selective presaturation of fat protons. It is commonly used because of its selectivity for fat, high SNR and relatively fast examination time. However, inhomogeneous fat suppression frequently occurs due to its B0- and B1-sensitivity, mostly in anatomical areas with challenging geometric features such as hands.
The Dixon method was first described in the early 1980s like the CHESS and STIR techniques . It is based on the acquisitions of in-phase and out-of-phase images during the same acquisition with secondary production of ‘water-only’ (i.e. fat-suppressed) and ‘fat-only’ (i.e. water-suppressed) images by post-processing (Figure 2) . The acquisition time of Dixon sequences is slightly longer than fat-suppressed sequences using different techniques due to the necessity to acquire the signal at different echo times. Fat-water swapping is an artifact specific to the Dixon sequences. It originates from a natural ambiguity between fat and water peaks which may cause inverted calculation between fat- and water-only voxels and is more frequent using the 2-point than the multi-point (>2) Dixon method .
For years, the post-processing time was excessively long and not suitable for use in clinical practice. In the mid 2000s, increased computer performances and other advances in hardware and software allowed drastic reduction of the time needed for post-processing. Since then, interest for the Dixon constantly grew with numerous studies demonstrating its robust homogeneous fat suppression and good image quality in the spine and large joints [41, 42, 43, 44, 45].
OMERACT recommendations specifically mention that fat-suppressed T2-weighted images of rheumatoid hands can be obtained either with the CHESS technique i.e. ‘fat saturation’ or with the STIR sequence [31, 33]. Fat-suppressed T1-weighted images after contrast-material injection are not specifically recommended by the OMERACT despite its common use in clinical practice and research studies [18, 35, 46, 47, 48].
We hypothesized that an MRI protocol including three-point Dixon sequences could yield more effective fat suppression and higher image quality than the current recommended sequences while accurately assessing disease activity. We tested the hypothesis that an MRI protocol exclusively based on sequences using the three-point Dixon method was suitable to assess rheumatoid hands and evaluate disease activity according to RAMRIS.
As a first result, our studies consistently demonstrated more robust fat suppression and higher image quality with Dixon- than with CHESS-based MRI protocols to image hands of healthy subjects (Figure 3) [49, 50] and RA patients at the cost of a longer imaging time .
Second, we compared a set of multiple Dixon-based MRI sequences with the recommended set of multiple CHESS-based MRI sequences in a series of 56 hands of patients with suspicion of early RA and demonstrated very good agreement between the two protocols for the assessment of synovitis, tenosynovitis, osteitis and erosions .
Then, we compared the scores of disease activity obtained in 48 hands of early RA patients by using either contrast-enhanced T1-weighted Dixon fat- and water-only images or the recommended non-Dixon MRI sequences and demonstrated similar results with the two protocols for the assessment of disease activity suggesting that a short Dixon-based MRI protocol only based on contrast-enhanced T1-weighted images can be used for early RA assessment .
Finally, we compared the measurability of hand cartilage using the Dixon sequences in normal subjects and in RA patients. Out of the four available T1-weighted Dixon images, joint-space width measurements performed on Dixon out-of-phase images had the highest correlation coefficient with those on radiographs (Figure 4) .
The authors have no competing interests to declare.
Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res. 2002; 4(Suppl 3): S265–72. DOI: https://doi.org/10.1186/ar578
Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. The Lancet. 2016; 388(10055): 2023–38. DOI: https://doi.org/10.1016/S0140-6736(16)30173-8
Upchurch KS, Kay J. Evolution of treatment for rheumatoid arthritis. Rheumatology (Oxford). 2012; 51(Suppl 6): vi28–36. DOI: https://doi.org/10.1093/rheumatology/kes278
Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988; 31(3): 315–24. DOI: https://doi.org/10.1002/art.1780310302
Nieuwenhuis WP, de Wit MP, Boonen A, van der Helm-van Mil AH. Changes in the clinical presentation of patients with rheumatoid arthritis from the early 1990s to the years 2010: Earlier identification but more severe patient reported outcomes. Ann Rheum Dis. 2016; 75(11): 2054–6. DOI: https://doi.org/10.1136/annrheumdis-2016-209949
Aga AB, Lie E, Uhlig T, et al. Time trends in disease activity, response and remission rates in rheumatoid arthritis during the past decade: Results from the NOR-DMARD study 2000–2010. Ann Rheum Dis. 2015; 74(2): 381–8. DOI: https://doi.org/10.1136/annrheumdis-2013-204020
Rubin DA. MR and ultrasound of the hands and wrists in rheumatoid arthritis. Part II. Added clinical value. Skeletal Radiol. 2019; 48(6): 837–57. DOI: https://doi.org/10.1007/s00256-019-03180-6
Aletaha D, Neogi T, Silman AJ, et al. 2010 rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010; 69(9): 1580–8. DOI: https://doi.org/10.1136/ard.2010.138461
Rubin DA. MRI and ultrasound of the hands and wrists in rheumatoid arthritis. I. Imaging findings. Skeletal Radiol. 2019; 48(5): 677–95. DOI: https://doi.org/10.1007/s00256-019-03179-z
McQueen FM, Benton N, Perry D, et al. Bone edema scored on magnetic resonance imaging scans of the dominant carpus at presentation predicts radiographic joint damage of the hands and feet six years later in patients with rheumatoid arthritis. Arthritis Rheum. 2003; 48(7): 1814–27. DOI: https://doi.org/10.1002/art.11162
Tamai M, Kawakami A, Uetani M, et al. The presence of anti-cyclic citrullinated peptide antibody is associated with magnetic resonance imaging detection of bone marrow oedema in early stage rheumatoid arthritis. Ann Rheum Dis. 2006; 65(1): 133–4. DOI: https://doi.org/10.1136/ard.2005.04138
McQueen FM, Ostendorf B. What is MRI bone oedema in rheumatoid arthritis and why does it matter? Arthritis Res Ther. 2006; 8(6): 222. DOI: https://doi.org/10.1186/ar2075
Tamai M, Kawakami A, Uetani M, et al. Bone edema determined by magnetic resonance imaging reflects severe disease status in patients with early-stage rheumatoid arthritis. J Rheumatol. 2007; 34(11): 2154–7.
Haavardsholm EA, Boyesen P, Ostergaard M, Schildvold A, Kvien TK. Magnetic resonance imaging findings in 84 patients with early rheumatoid arthritis: Bone marrow oedema predicts erosive progression. Ann Rheum Dis. 2008; 67(6): 794–800. DOI: https://doi.org/10.1136/ard.2007.071977
Schwenzer NF, Kotter I, Henes JC, et al. The role of dynamic contrast-enhanced MRI in the differential diagnosis of psoriatic and rheumatoid arthritis. AJR Am J Roentgenol. 2010; 194(3): 715–20. DOI: https://doi.org/10.2214/AJR.09.2671
Cimmino MA, Innocenti S, Livrone F, Magnaguagno F, Silvestri E, Garlaschi G. Dynamic gadolinium-enhanced magnetic resonance imaging of the wrist in patients with rheumatoid arthritis can discriminate active from inactive disease. Arthritis Rheum. 2003; 48(5): 1207–13. DOI: https://doi.org/10.1002/art.10962
Meier R, Thuermel K, Noel PB, et al. Synovitis in patients with early inflammatory arthritis monitored with quantitative analysis of dynamic contrast-enhanced optical imaging and MR imaging. Radiology. 2014; 270(1): 176–85. DOI: https://doi.org/10.1148/radiol.13130039
Stomp W, Krabben A, van der Heijde D, et al. Aiming for a simpler early arthritis MRI protocol: can Gd contrast administration be eliminated? Eur Radiol. 2015; 25(5): 1520–7. DOI: https://doi.org/10.1007/s00330-014-3522-1
Li X, Liu X, Du X, Ye Z. Diffusion-weighted MR imaging for assessing synovitis of wrist and hand in patients with rheumatoid arthritis: A feasibility study. Magn Reson Imaging. 2014; 32(4): 350–3. DOI: https://doi.org/10.1016/j.mri.2013.12.008
Ramalho J, Semelka RC, Ramalho M, Nunes RH, AlObaidy M, Castillo M. Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update. AJNR Am J Neuroradiol. 2016; 37(7): 1192–8. DOI: https://doi.org/10.3174/ajnr.A4615
Bower DV, Richter JK, von Tengg-Kobligk H, Heverhagen JT, Runge VM. Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent. Invest Radiol. 2019; 54(8): 453–63. DOI: https://doi.org/10.1097/RLI.0000000000000567
Axelsen MB, Eshed I, Duer-Jensen A, Moller JM, Pedersen SJ, Ostergaard M. Whole-body MRI assessment of disease activity and structural damage in rheumatoid arthritis: First step towards an MRI joint count. Rheumatology (Oxford). 2014; 53(5): 845–53. DOI: https://doi.org/10.1093/rheumatology/ket425
Axelsen MB, Eshed I, Ostergaard M, et al. Monitoring total-body inflammation and damage in joints and entheses: The first follow-up study of whole-body magnetic resonance imaging in rheumatoid arthritis. Scand J Rheumatol. 2017; 46(4): 253–62. DOI: https://doi.org/10.1080/03009742.2016.1231338
Chaudhari AJ, Ferrero A, Godinez F, et al. High-resolution (18)F-FDG PET/CT for assessing disease activity in rheumatoid and psoriatic arthritis: Findings of a prospective pilot study. Br J Radiol. 2016; 89(1063): 20160138. DOI: https://doi.org/10.1259/bjr.20160138
Pauk J, Wasilewska A, Ihnatouski M. Infrared Thermography Sensor for Disease Activity Detection in Rheumatoid Arthritis Patients. Sensors (Basel). 2019; 19(16). DOI: https://doi.org/10.3390/s19163444
Klarenbeek NB, Guler-Yuksel M, van der Heijde DM, et al. A comparison between the simplified erosion and narrowing score and the Sharp-van der Heijde score: Post hoc analysis from the Best study. Ann Rheum Dis. 2011; 70(4): 714–6. DOI: https://doi.org/10.1136/ard.2010.134346
D’Agostino MA, Terslev L, Aegerter P, et al. Scoring ultrasound synovitis in rheumatoid arthritis: A EULAR-OMERACT ultrasound taskforce-Part 1: definition and development of a standardised, consensus-based scoring system. RMD Open. 2017; 3(1): e000428. DOI: https://doi.org/10.1136/rmdopen-2016-000428
do Prado AD, Staub HL, Bisi MC, et al. Ultrasound and its clinical use in rheumatoid arthritis: Where do we stand? Adv Rheumatol. 2018; 58(1): 19. DOI: https://doi.org/10.1186/s42358-018-0023-y
Ostergaard M, Peterfy C, Conaghan P, et al. OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging Studies. Core set of MRI acquisitions, joint pathology definitions, and the OMERACT RA-MRI scoring system. J Rheumatol. 2003; 30(6): 1385–6.
Glinatsi D, Bird P, Gandjbakhch F, et al. Development and Validation of the OMERACT Rheumatoid Arthritis Magnetic Resonance Tenosynovitis Scoring System in a Multireader Exercise. J Rheumatol; 2017. DOI: https://doi.org/10.3899/jrheum.161097
Ostergaard M, Peterfy CG, Bird P, et al. The OMERACT Rheumatoid Arthritis Magnetic Resonance Imaging (MRI) Scoring System: Updated Recommendations by the OMERACT MRI in Arthritis Working Group. J Rheumatol. 2017; 44(11): 1706–12. DOI: https://doi.org/10.3899/jrheum.161433
Bird P, Conaghan P, Ejbjerg B, et al. The development of the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas. Ann Rheum Dis. 2005; 64(Suppl 1): i8–10. DOI: https://doi.org/10.1136/ard.2004.031807
B. CCMAHDDJ-PMXC. Rheumatoid Arthritis of the Hand: Monitoring with a Simplified MR Imaging Scoring Method— Preliminary Assessment. Radiology. 2010; 256(3): 863–9. DOI: https://doi.org/10.1148/radiol.10091759
Frenken M, Schleich C, Brinks R, et al. The value of the simplified RAMRIS-5 in early RA patients under methotrexate therapy using high-field MRI. Arthritis Res Ther. 2019; 21(1): 21. DOI: https://doi.org/10.1186/s13075-018-1789-3
Chand AS, McHaffie A, Clarke AW, et al. Quantifying synovitis in rheumatoid arthritis using computer-assisted manual segmentation with 3 Tesla MRI scanning. J Magn Reson Imaging. 2011; 33(5): 1106–13. DOI: https://doi.org/10.1002/jmri.22524
Del Grande F, Santini F, Herzka DA, et al. Fat-suppression techniques for 3-T MR imaging of the musculoskeletal system. Radiographics: A review publication of the Radiological Society of North America, Inc. 2014; 34(1): 217–33. DOI: https://doi.org/10.1148/rg.341135130
Dixon WT. Simple proton spectroscopic imaging. Radiology. 1984; 153(1): 189–94. DOI: https://doi.org/10.1148/radiology.153.1.6089263
Kirchgesner T, Acid S, Perlepe V, Lecouvet F, Vande Berg B. Two-point Dixon fat-water swapping artifact: Lesion mimicker at musculoskeletal T2-weighted MRI. Skeletal Radiol; 2020. DOI: https://doi.org/10.1007/s00256-020-03512-x
Guerini H, Omoumi P, Guichoux F, et al. Fat Suppression with Dixon Techniques in Musculoskeletal Magnetic Resonance Imaging: A Pictorial Review. Semin Musculoskelet Radiol. 2015; 19(4): 335–47. DOI: https://doi.org/10.1055/s-0035-1565913
Brandao S, Seixas D, Ayres-Basto M, et al. Comparing T1-weighted and T2-weighted three-point Dixon technique with conventional T1-weighted fat-saturation and short-tau inversion recovery (STIR) techniques for the study of the lumbar spine in a short-bore MRI machine. Clin Radiol. 2013; 68(11): e617–23. DOI: https://doi.org/10.1016/j.crad.2013.06.004
Park HJ, Lee SY, Rho MH, et al. Usefulness of the fast spin-echo three-point Dixon (mDixon) image of the knee joint on 3.0-T MRI: Comparison with conventional fast spin-echo T2 weighted image. Br J Radiol. 2016; 89(1062): 20151074. DOI: https://doi.org/10.1259/bjr.20151074
Ma J, Singh SK, Kumar AJ, Leeds NE, Zhan J. T2-weighted spine imaging with a fast three-point dixon technique: Comparison with chemical shift selective fat suppression. J Magn Reson Imaging. 2004; 20(6): 1025–9. DOI: https://doi.org/10.1002/jmri.20201
Tagliafico A, Bignotti B, Tagliafico G, Martinoli C. Usefulness of IDEAL T2 imaging for homogeneous fat suppression and reducing susceptibility artefacts in brachial plexus MRI at 3.0 T. Radiol Med. 2016; 121(1): 45–53. DOI: https://doi.org/10.1007/s11547-015-0576-3
Stomp W, Krabben A, van der Heijde D, et al. Aiming for a shorter rheumatoid arthritis MRI protocol: Can contrast-enhanced MRI replace T2 for the detection of bone marrow oedema? Eur Radiol. 2014; 24(10): 2614–22. DOI: https://doi.org/10.1007/s00330-014-3272-0
Boutry N, Hachulla E, Flipo RM, Cortet B, Cotten A. MR imaging findings in hands in early rheumatoid arthritis: Comparison with those in systemic lupus erythematosus and primary Sjogren syndrome. Radiology. 2005; 236(2): 593–600. DOI: https://doi.org/10.1148/radiol.2361040844
Kirchgesner T, Perlepe V, Michoux N, Larbi A, Vande Berg B. Fat suppression at 2D MR imaging of the hands: Dixon method versus CHESS technique and STIR sequence. European Journal of Radiology. 2017; 89: 40–6. DOI: https://doi.org/10.1016/j.ejrad.2017.01.011
Kirchgesner T, Perlepe V, Michoux N, Larbi A, Vande Berg B. Fat suppression at three-dimensional T1-weighted MR imaging of the hands: Dixon method versus CHESS technique. Diagn Interv Imaging. 2018; 99(1): 23–8. DOI: https://doi.org/10.1016/j.diii.2017.09.004
Kirchgesner T, Stoenoiu M, Michoux N, Durez P, Vande Berg B. Comparison between 3-point Dixon- and CHESS-based OMERACT-recommended MRI protocols in hands of patients with suspicion of early rheumatoid arthritis. Eur J Radiol. 2021; 134: 109412. DOI: https://doi.org/10.1016/j.ejrad.2020.109412
Kirchgesner T, Stoenoiu M, Michoux N, Durez P, Vande Berg B. Contrast-enhanced T1-weighted Dixon water- and fat-only images to assess osteitis and erosions according to RAMRIS in hands of patients with early rheumatoid arthritis. Diagn Interv Imaging; 2021. DOI: https://doi.org/10.1016/j.diii.2021.01.011
Kirchgesner T, El Kassimy A, Michoux N, Stoenoiu M, Durez P, Vande Berg B. India ink artifact on Dixon out-of-phase images can be used as a landmark to measure joint space width at MRI. Diagn Interv Imaging; 2021. DOI: https://doi.org/10.1016/j.diii.2021.09.010
Bley TA, Wieben O, Francois CJ, Brittain JH, Reeder SB. Fat and water magnetic resonance imaging. J Magn Reson Imaging. 2010; 31(1): 4–18. DOI: https://doi.org/10.1002/jmri.21895