Rheumatology 2014;53:845–853 doi:10.1093/rheumatology/ket425 Advance Access publication 3 January 2014

RHEUMATOLOGY

Original article Whole-body MRI assessment of disease activity and structural damage in rheumatoid arthritis: first step towards an MRI joint count Mette Bjørndal Axelsen1,2, Iris Eshed3, Anne Duer-Jensen4, Jakob M. Møller5, Susanne Juhl Pedersen6 and Mikkel Østergaard1,2

Methods. The 3T WBMR images were acquired in a head-to-toe scan in 20 patients with RA and at least one swollen or tender joint. Short Tau Inversion Recovery and pre- and post-contrast T1-weighted images were evaluated for readability and the presence/absence of inflammation (synovitis, BME and enthesitis) and structural damage (erosions and fat infiltrations) in 76 peripheral joints, 30 entheseal sites and in the spine. Results. The readability was >70% for all individual joints, except for the most peripheral joints of the hands and feet. Synovitis was most frequent in the wrist, first tarsometatarsal, first CMC joints and glenohumeral joints (67–61%); BME in the wrist, CMC, acromioclavicular and glenohumeral joints (45–35%) and erosions in the wrist, MTP and CMC joints (19–16%). Enthesitis at 51 site was registered in 16 patients. BME was frequently seen in the cervical (20%) but not the thoracic and lumbar spine, while fat infiltrations and erosions were rare. The intrareader agreement was high (85–100%) for all pathologies. The agreement between WBMRI and clinical findings was low. Conclusion. Peripheral and axial inflammation and structural damage at joints and entheses was frequently identified by WBMRI, and more frequently than by clinical examination. WBMRI is a promising tool for evaluation of the total inflammatory load of inflammation (an MRI joint count) and structural damage in RA patients. Key words: rheumatoid arthritis, magnetic resonance imaging, whole-body imaging, inflammation, structural damage.

Introduction 1 Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital at Glostrup, 2 Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen University, Copenhagen, Denmark, 3 Department of Radiology, Sheba Medical Center, Tel Hashomer, Tel Aviv University, Tel Aviv, Israel, 4Department of Radiology, Copenhagen University Hospital at Hvidovre, 5Department of Radiology, Copenhagen University Hospital at Herlev, and 6 Department of Rheumatology, Copenhagen University Hospital at Gentofte, Denmark.

Submitted 29 April 2013; revised version accepted 31 October 2013. Correspondence to: Mette Bjørndal Axelsen, Copenhagen Center for Arthritis Research, Center for Rheumatology and Spine Diseases, Copenhagen University Hospital at Glostrup, Nordre Ringvej 57, Opgang 5, 2600 Glostrup, Denmark. E-mail: [email protected]

RA is a systemic inflammatory disease involving peripheral and occasionally axial joints. Conventional MRI of peripheral joints is more sensitive than clinical examination for detecting disease activity [1, 2] and allows monitoring of disease activity and prediction of subsequent structural damage in RA [3, 4]. The utility of MRI and other imaging modalities in the clinical management of RA was described in recent European League Against Rheumatism (EULAR) recommendations based on a systemic literature review [5]. MRI of a few joints, most often unilateral wrist and second to fifth MCP joints is a sensitive and reliable method for assessing inflammation and

! The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]

CLINICAL SCIENCE

Objective. The aim of this study was to investigate the ability of whole-body MRI (WBMRI) to visualize inflammation [synovitis, bone marrow oedema (BME) and enthesitis] and structural damage in patients with RA.

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Abstract

Mette Bjørndal Axelsen et al.

Patients and methods Patients The study population comprised 20 (14 women, 6 men) patients with RA (Table 1). The inclusion criteria were RA according to the ACR 1987 classification criteria [16] and active disease, defined as at least one swollen or tender joint at clinical examination. Exclusion criteria were contraindications for undergoing contrast-enhanced MRI, including impaired kidney function (serum creatinine above the upper limit of normal) and pregnancy or breastfeeding. Furthermore, changes in glucocorticoid dosage, including intra-articular or intramuscular injections with glucocorticoid, were not allowed within 4 weeks before the clinical examination and MRI scan. The clinical examination included tender and swollen joint counts of 68 and 66 joints, respectively; physical function was measured using the HAQ and visual analogue scale (VAS) for assessment of the patient’s global health and for doctor’s assessment of the patient’s global health. Biochemical analyses included serum CRP, and the 28-joint DAS (DAS28) was calculated. Within 1 week of the clinical examination a 3T WBMRI was performed. All patients signed informed consent before participation. The study complied with the Declaration of Helsinki and was approved by the Committees on Biomedical Research Ethics for the Capital Region of Denmark.

MRI procedure The WBMRI was performed on a 3T Philips Achieva system using the integrated transmit/receive Quadrature body coil (Philips Healthcare, Best, The Netherlands). The patients were placed in a supine position, feet first. T1-weighted spin echo (SE) sequences before and after an i.v. gadolinium-containing contrast injection (Dotarem, Guerbet, France; 0.1 mmol/kg body weight) and a Short Tau Inversion Recovery (STIR) sequence were acquired at

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TABLE 1 Patient characteristics Number (women/men) Age, median (range), years Disease duration, median (range), years VAS global, median (range) CRP, median (range), mg/l DAS28-CRP(4), median (range) Number of tender joints (of 68), median (range) Number of swollen joints (of 66), median (range) HAQ, median (range) VAS doctor, median (range) IgM RF (positive/negative) Anti-CCP (positive/negative)

20 (14/6) 54 (21–76) 6 (1–20) 34.5 (10–94) 7 (1–15) 4.30 (1.91–7.32) 13 (0–40) 4 (0–21) 1.38 (0.00–2.63) 37 (0–88) 18/2 6/1 (unknown 13)

six scanning stations covering the feet, knees, pelvis, lumbar spine, thoracic spine and shoulders and the cervical spine. Table 2 shows the technical parameters of the MRI scan. The total scan time was 60 min per patient. During scanning of the pelvis, which took 3.5–4.5 min per sequence, the patients were asked to place their hands underneath the pelvis with the first finger medially. The patients were allowed to place the hands elsewhere during scanning of the five other stations. The maximum time the patients were lying on their hands was 5 min at a time. All patients accepted the scanning procedure.

Image evaluation Seventy-six peripheral joints, 23 discovertebral units (DVUs), 2 SI joints and 30 entheseal sites were evaluated in each patient. The 76 peripheral joints examined (Fig. 1) were the bilateral sternoclavicular, acromioclavicular, glenohumeral, elbow, wrist, first CMC, first–fifth MCP, first IP, second–fifth PIP, second–fifth DIP, hip, knee, ankle, first tarsometatarsal (TMT), first–fifth MTP, first–fifth PIP and second–fifth DIP joints of the feet. DVUs from C2/C3–L5/S1 were evaluated, divided in ventral/posterior parts. A DVU was defined as the region between two horizontal lines drawn across the midpoint of adjacent vertebrae in the sagittal orientation. Similarly, the SI joints were evaluated divided in the upper and lower iliac and upper and lower sacral quadrants. The entheseal sites were the bilateral first and seventh sternocostal joint, greater humeral tuberosity, humeral ulnar and radial condyles, anterior and posterior superior iliac spine, iliac crest, ischial tuberosity, femoral greater trochanter, medial femoral condyle, patellar base, patellar apex, tibial tuberosity and Achilles tendon insertion at the calcaneus (Fig. 1). The image quality for each anatomical area was assessed as not imaged, the anatomy was not in the field of view; image quality poor, the anatomy was in the field of view, but the image quality was too poor for evaluation of pathologies or image quality good. Images of good quality were readable. In the intra-agreement analysis we further subdivided the scores on image quality into a 6-point scale as follows: 0, anatomy not in field of view; 1, very

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structural damage [6–8], but when using this few-jointsapproach, multiple joint disease and subclinical disease activity may be overlooked. Whole-body MRI (WBMRI) is a method that allows imaging of the entire body in one scanning session. WBMRI is used in oncology for assessing tumour spread and metastases [9]. In rheumatology, WBMRI is a promising tool in assessing the axial joints [10, 11], and peripheral joints and entheses [12–15] in SpA. WBMRI could also be a useful tool in RA because of the frequent involvement of multiple peripheral joints and the cervical spine, potentially providing a measure of the total inflammatory load, an MRI joint count. However, no studies on WBMRI in an RA cohort have been reported and the clinical utility of this new imaging method is not known. The aim of this study was to investigate the ability of WBMRI to visualize inflammation [synovitis, bone marrow oedema (BME) and enthesitis] and structural damage (erosions and fat infiltration) in patients with RA and to examine the agreement between findings from WBMRI and clinical examination.

Whole-body MRI in RA

TABLE 2 Technical parameter of whole-body MRI

Section

Knees

Axial

Coronal

Coronal

Coronal

Coronala

Sagittal

5 732.9 7.6 576  576 472  472 0.82 6 4.32

3 1191 7.6 576  576 472  472 0.82 4 1.52

5 732.9 7.6 576  576 472  472 0.82 6 1.52

4 916.2 7.6 576  576 472  472 0.82 5 2.15

5 5915 70 200 320  320 470  470 1.47 6 4.38

3 13905 82.9 200 480  480 480  480 1 4 1.03

5 5258 70 200 320  320 470  470 1.47 4 1.03

5 5258 70 200 320  320 470  470 1.47 6 1.03

T1-weighted spin echo before and after contrast Slice thickness, mm 3 3 TR, ms 1100 1100 TE, ms 7.6 7.6 Matrix 576  576 576  576 FOV, mm 472  472 472  472 Pixel spacing, mm 0.82 0.82 Slice spacing, mm 4 4 Time of sequence, min 3.37 1.52 STIR Slice thickness, mm 3 5 TR, ms 5258 5258 TE, ms 70 70 Inversion time, ms 200 200 Matrix 320  320 320  320 FOV, mm 470  470 470  470 Pixel spacing, mm 1.47 1.5 Slice spacing, mm 4 6 Time of sequence, min 3.19 1.11

Lumbar spine

Thoracic spine and shoulder

Cervical and upper thoracic spine

TR: relaxation time; TE: echo time; FOV: field of view. aIn cases where the spine was not covered in a single FOV, an extra coronal sequence was obtained in the cervical scanning station.

poor image quality; 2, poor image quality; 3, acceptable image quality; 4, good image quality; 5, very good image quality. Image quality of 0–2 was not readable, while 3–5 was readable and scored for pathologies. For all readable areas, pathologies were registered as present or absent (1 or 0). For both peripheral and axial areas, pathology definitions were based on definitions proposed in previous international collaborations [6, 17, 18]. Synovitis was defined as an area in the synovial compartment that showed above-normal post-gadolinium enhancement on T1-weighted images of a thickness greater than the width of the normal synovium. BME was defined as a lesion within the trabecular bone, with ill-defined margins and signal characteristics consistent with increased water content, i.e. high signal intensity on STIR images and low signal intensity on T1-weighted images. Bone erosions were defined as bone lesions with correct localization and a cortical break, i.e. loss of normal low signal intensity of cortical bone and loss of normal high signal intensity of adjacent bone marrow on T1-weighted images. Enthesitis was defined as an area at the entheseal site with increased signal intensity on a STIR or a postgadolinium T1-weighted sequence compared with the normal signal intensity of the entheseal site. Focal fat infiltration was defined as focal increased signal intensity on T1-weighted images and low signal intensity on the STIR images in the bone marrow, at the vertebral corners or in the iliac or sacral bone adjacent to the SI joint [17]. One musculoskeletal radiologist experienced with conventional and WBMRI (I.E.) evaluated all images blinded to clinical data, using a 15-inch high-resolution screen and

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the imaging processing software ClearCanvas, version 2.0 (ClearCanvas, Toronto, ON, Canada). The average reading time per image set was 60 min. The intra-reader agreement was assessed by anonymizing 10 sets of images twice and rescoring them as described above.

Statistics Descriptive and non-parametric statistics were used. Agreement between imaging and clinical findings was tested using kappa values for individual joints and Spearman’s rank correlation coefficient between MRI and clinical joint counts. SPSS, version 19 (SPSS, Chicago, IL, USA), was used for the statistical analyses.

Results Patient characteristics The patients’ characteristics are presented in Table 1. All patients were treated with anti-inflammatory drugs at inclusion: nine patients received MTX monotherapy, one patient HCQ monotherapy, two patients combination MTX and SSZ therapy, six patients TNF inhibitor (TNFi), all but one in combination with DMARDs, and one patient rituximab monotherapy. Three patients received oral prednisolone 2.5–5 mg/day as part of combination therapy with TNFi (2) or MTX (1). Prior to current treatment, all patients but 1 had received one to three different DMARDs, 8 had received oral prednisolone, 13 had received intra-articular or intra-muscular injections with glucocorticoids and 7

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Feet

Pelvis, hip, SI joints and hands

Mette Bjørndal Axelsen et al.

FIG. 1 Readability and frequencies for synovitis, BME, erosions and enthesitis

had received one to three different TNFis prior to current treatment.

Image quality Fig. 1A shows the readability for synovitis, BME, erosions and enthesitis for the peripheral joints and the entheses. The readability was good (>80%) for all large peripheral joints except the elbows (25–50%). For the hands and feet, >70% of the proximal joints and the peripheral joints placed medially in the scanner had a good readability, whereas fewer of the peripheral joints placed laterally in the scanner had good readability (for the hands, the thumb was placed medially). Images were most frequently readable for bone erosions, followed by synovitis and BME. The readability was good for pelvic entheseal sites (100% of sites), the medial femoral condyles and the tendon insertion at the calcaneus (Achilles tendons), but it was low for the humeral condyles and the entheseal sites at the patellar apex and the tibial tuberosity. In the axial skeleton, all DVUs and >90% of SI joint quadrants could be read.

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A joint not imaged was the main reason for compromised readability for synovitis and BME, except in the DIP joints of the feet and for BME in the DIP joints of the hands, where the readability was compromised by poor image quality in up to half of the not readable joints. For erosions, poor image quality was the reason in only nine joints, whereas joints not imaged was the reason in the rest of the sites not read. Concerning entheseal sites, the image quality was too low for evaluation in 15 of 19 unread cases at the patellar apex and in 17 of 20 unread cases at the tibial tuberosity bilaterally. At the remaining entheseal sites, all unread cases were due to sites not imaged.

WBMRI findings Table 3 shows the number of patients with synovitis, BME, bone erosions and fat infiltrations in peripheral and axial joints and inflammation at entheseal sites. Synovitis was found in all patients (52 joints in all patients), BME in all but 1 patient (a median of 10 bones affected) and enthesitis in 16 of the patients (a median 2 entheseal sites were

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(A) Proportion (%) of peripheral joints and entheseal sites that were readable, presented separately for synovitis, BME, bone erosions and enthesitis. (B) Frequency (%) of synovitis, BME, erosions and enthesitis in readable joints and entheseal sites. The colour codes for each interval of percentage in (A) and (B) are presented to the right.

Whole-body MRI in RA

TABLE 3 Number of patients with synovitis, BME, enthesitis, bone erosions and fat infiltrations on WBMRI in peripheral and axial joints

Pathology

20 19 12

16 (2–33) 10 (0–20) 3 (0–24)

16

2 (0–12)

4 4 3 3 0 0 2 1 2 0 2 1

0 0 0 0 0 0 0 0 0 0 0 0

Peripheral synovial joints Synovitis BME Erosion Entheseal sites Enthesitis Axial joints BME Cervical spine Thoracic spine Lumbar spine SI joints Erosion Cervical spine Thoracic spine Lumbar spine SI joints Fat infiltration Cervical spine Thoracic spine Lumbar spine SI joints

involved). In the spine, BME was found in eight patients and was the most frequent pathology. Fat infiltration and erosions were found in three and two patients, respectively. Table 4 shows the frequency of WBMRI synovitis, BME and bone erosions. In the peripheral joints, synovitis was registered in all types of joint, except for the DIP joints. Synovitis was most frequently found in wrist joints (67%), followed by TMT, CMC, glenohumeral, AC and ankle joints (550%). The location of BME showed the same joint pattern, but was less frequent. Erosions were most frequently found in wrist (19%) and MTP (18%) joints, followed by the CMC, glenohumeral, MCP and PIP, knee, ankle and TMT joints (5–16% of the readable cases; Table 4). MRI enthesitis was particularly detected at the insertions at the greater trochanter (60%) and the ischial tuberosity (39%), followed by the greater humeral tuberosity (26%) and the calcaneus (25%) (Fig. 1B). Examples of typical inflammatory and structural findings are shown in Fig. 2. In the spine, pathologies were found mainly in the cervical spine (45%) followed by the lumbar (38%) and thoracic (17%) spine.

Intrareader agreement The readability for the 10 image sets read twice was similar to that of the main image set (data not shown). The presence and absence of synovitis, BME and erosion in the hands/feet was scored the same in the two readings in 91%/90%, 93%/89% and 99%/98% of the sites. The percentage agreement for the sternoclavicular and acromioclavicular joints, shoulders, elbows, hips and knees together was 85%, 87% and 99% for synovitis, BME

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(0–3) (0–2) (0–3) (0–2)

(0–2) (0–2) (0–3) (0–1) (0–4)

and erosions. All pathologies in the SI joints were scored the same in the two readings (agreement 100%) except for fat infiltration at one location. In the spine the agreement was 98%, 97% and 99% for BME, fat infiltration and bone erosions, respectively, and the readings of enthesitis agreed in 92% of the cases. The image quality assessed using a 6-point scale (very good, good, acceptable, poor, very poor, not in the field of view) showed that a very good image quality was obtained for 10% of the SI joints, but only 0–3% of all other joints. For the hands and feet the image quality was good in 0–25%, acceptable in 37–94%, poor in 0–27%, very poor in 1–35% and the joints were not in field of view in 0–13% of the cases. For the proximal peripheral joints the image quality was good for 33–34%, acceptable for 29–40%, poor for 2–3%, very poor for 4% and the joints were not in the field of view in 17–28% of the cases. For the entheseal sites the image quality was good, acceptable, poor or very poor in 15%, 37%, 3% and 24% of the cases, respectively. In 18% of the cases, the entheseal sites were not in the field of view. For the SI joints, the image quality was good for 10–20% and acceptable for 70–80% of the SI joints. All SI joints were readable. In the spine the image quality was good in 0–5% and acceptable in 94–100% of the cases. Only 0–1% of the spine lesions were not read because of a poor image quality.

The relationship between WBMRI and clinical evaluation Table 4 provides the frequencies of clinical swelling and tenderness per joint. The median number of tender and swollen joints per patient were 13 and 4 (ranges 0–40 and

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Number of patients with MRI changes

Number of peripheral joints/DVUs/sacroiliac quadrants with MRI changes per patient, median (minimum–maximum)

Mette Bjørndal Axelsen et al.

TABLE 4 Frequency (percentage per joint) of WBMRI synovitis, BME and bone erosions and of clinical swelling and tenderness in peripheral joints WBMRI evaluation

Clinical evaluation

Synovitis

BME

Erosion

Sternoclavicular Acromioclavicular Glenohumeral Elbow Wrist CMC 1 MCP 1–5 PIP 2–5 DIP 2–5 Hip Knee Ankle TMT 1 MTP 1–5 PIPF 1–5 DIPF 1–5

0 50 61 23 67 61 28 (27–39) 15 (3–25) 0 25 45 50 62.5 35 (31–49) 10 (0–15) 0 (0–3)

0 35 33 8 45 36 12 (7–27) 7 (4–13) 0 10 26 7.5 37.5 31 (13–47) 9 (0–20) 0

0 0 10 0 19 16 3 (0–16) 3 (3–6) 0 0 8 5 10 18 (8–31) 0 0

Tenderness 11 — 33 17 36 19 27 32 13 17 47 47 — 37 1 —

(17–33) (28–39) (8–17)

(22–51) (0–6)

Swelling 1 — 6 8 19 0 21 12 1 — 8 28 — 8 0 —

(6–37) (3–14) (0–3)

(0–14) (0–0)

Numbers are presented as medians (for MCP, PIP, DIP, MTP, PIPF and DIPF joints they are presented as median (range). CMC 1: first carpometacarpal joint; MCP 1–5: first–fifth metacarpal joints; PIP 2–5: second–fifth proximal interphalangeal joints; DIP2–5: second–fifth distal interphalangeal joints; TMT: first tarsometatarsal joints; MTP 1–5: first–fifth metatarsophalangeal joints; PIPF 1–5: first–fifth proximal interphalangeal joints in the feet; DIPF 1–5: first–fifth distal interphalangeal joints in the feet.

0–21), respectively. Tenderness was more frequent than swelling, and 47% of the knee and ankle joints and >35% of the MTP and wrist joints were tender, while swelling was most frequent in the ankle, MCP, and wrist joints, with 519% of the joints involved. At the joint level, WBMRI synovitis and BME showed low agreement with clinical tenderness [k = 0.12 ( 0.36–0.59) and 0.00 ( 0.35–0.35), respectively] and clinical swelling [k = 0.04 ( 0.29–1.00) and 0 ( 0.98–1), respectively]. Comparing clinical 28-joint counts of tender, swollen and tender and/or swollen joints versus 28-joint counts of synovitis, BME, and synovitis and BME showed low correlations between the two methods (data not shown).

Discussion In this cross-sectional study of WBMRI in patients with established RA we demonstrated good readability in all axial and peripheral joints, except the DIP and PIP joints of the feet and the elbows. The readability was equally high for entheseal sites, except for those of the knee. WBMRI detected signs of disease activity and damage throughout the body in peripheral and axial joints and at entheseal sites. The readability of individual joints as assessed by WBMRI in RA has not previously been reported. Two studies using 1.5T contrast-enhanced WBMRI have assessed the readability (image quality and contrast) of joint regions in patients with PsA [14] and with

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undifferentiated arthritis [19]. Weckbach et al. [14] found that the image quality and contrast was good to excellent in the axial skeleton in 86.6% and good in the feet and hands of 53% of the 31 patients examined. Kamishima et al. [19] found that the image quality and contrast was excellent in the atlantoaxial, glenohumeral and hip joints in 17 (100%) patients. The image quality and contrast in the hands was good in 9 patients and excellent in 8 patients and excellent in the feet in 16 patients. In the present study we evaluated the readability for each individual joint and found a higher readability for both the axial and peripheral joints than in the two former studies. We used a 3T MRI unit with an integrated coil and with the hands placed under the pelvis during imaging. Using this method the readability was low for the elbows and the most peripheral and distal joints of the hands and feet. Low readability was most often due to an area not imaged rather than poor image quality. We used a built-in body coil in WBMRI and it was not possible to place all parts of the body centrally in the scanner, and the image quality was compromised in the joints of the hands and feet. It is a challenge to find the best positioning of the patient to allow all relevant areas to be imaged. This could be overcome by using specific coils for specific areas, but this would increase the scanning time. In future WBMRI studies both coverage and imaging settings such as slice orientation, slice thickness and slice gap must be optimized. We registered WBMRI synovitis and BME more frequently than clinically tender and swollen joints, and no

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Joint

Whole-body MRI in RA

FIG. 2 Inflammatory and structural MRI findings

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(A–D) T1-weighted images before (A and C) and after (B and D) an i.v. contrast injection of the ankle joint (A and B, axial images) and the glenohumeral joint (C and D, coronal images). Synovitis is seen as bright areas on post-contrast images (arrows). (E and F) Coronal STIR and post-contrast T1-weighted images of the wrist joint showing synovitis (arrow) and BME of the capitate (thick arrow in E and F). (G and H) Coronal STIR images of the right and left hip joints showing bilateral enthesitis (arrows).

statistically significant correlations between the two methods were found. Thus WBMRI detected disease activity more frequently than clinical examination. This is in agreement with previous studies of WBMRI in other diseases [14] and of conventional MRI [2]. Findings by conventional MRI have been shown to have high agreement with established standard reference methods, i.e. synovitis with histology [20, 21] and microarthoscopy [22], BME with histology [23, 24] and MRI erosions with computed tomography [25] and histology [23]. In contrast, there is no evidence that WBMRI findings truly represent disease activity. However, in patients with axial SpA, the correlation between WBMRI and conventional MRI findings of inflammatory lesions, as well as the intra- and interreader agreement, is high for both the spine [10] and the SI joints [11]. This supports findings on WBMRI representing real disease-related changes. Further studies with direct comparison with established standard reference methods as previously performed for conventional MRI are needed. This is the first study to investigate the presence of WBMRI enthesitis in patients with RA. Surprisingly, MRI enthesitis was registered in 16 patients. It has previously been suggested that enthesitis as visualized by MRI or ultrasonography can be used to differentiate between RA and SpA [26], and enthesitis has been found more frequently in SpA than in RA in finger (63% vs 33%) and knee joints (100% vs 0%) with active disease [27, 28]. Clinical enthesitis is one of the SpA features in the 2009 SpA classification criteria [29]. However, the frequency of enthesitis in RA and SpA is unknown and WBMRI may help to determine this. The MRI examination protocol lasted 60 min, which is too long for use in clinical practice, and a shorter scanning time is required. This may be possible by omitting certain areas of less importance, for instant, the thoracic and lumbar spine and the SI joints (i.e. two scan sections), where very few pathologies were found. Furthermore, sequence optimization and reduction of the number of MRI sequences are other options. In this study the imaging protocol included STIR and pre- and post-contrast T1-weighted sequences. Contrast enhanced images are recommended for scoring of synovitis in conventional MRI [30] and WBMRI [14]. Kamishima et al. [19] used only fatsuppressed post-contrast T1-weighted images, resulting in a scanning time of only 30 min. Whether such a protocol can be used to score all the pathologies scored in this study (synovitis, BME, enthesitis, fat infiltration and erosion) needs testing. Our preliminary test MRIs, done before the start of the study, showed that it was very difficult to make WBMR images with good fat suppression (data not shown), and we therefore did not use fatsuppressed images. Fat suppression is susceptible to inhomogeneities in the magnetic field, which may be present in the more peripheral parts of the scanner. Another option could be to use a STIR sequence, as this allows an overall impression of the inflammatory load (synovitis and BME), which may be the most important application for WBMRI in RA [30]. However, scoring of inflammation from STIR images alone has some limitations. Studies have

Mette Bjørndal Axelsen et al.

Rheumatology key messages Whole-body MRI (WBMRI) can visualize axial as well as peripheral joints in patients with RA. . Inflammation is detected more frequently by WBMRI than by clinical examination in RA. . With further optimization, WBMRI could be used as a future inflammation MRI joint count in RA. .

Disclosure statement: M.O. has received consulting fees, speaking fees and/or research grants from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Genmab, Glaxo-Smith-Kline, Mundipharma, Novo, Pfizer, Roche, Schering-Plough, UCB and Wyeth. S.J.P. has acted as a

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consultant for AbbVie, received speaker honoraria from AbbVie, Pfizer, UCB and MSD and received research support from AbbVie and MSD. All other authors have declared no conflicts of interest.

References 1 Brown AK, Quinn MA, Karim Z et al. Presence of significant synovitis in rheumatoid arthritis patients with diseasemodifying antirheumatic drug-induced clinical remission: evidence from an imaging study may explain structural progression. Arthritis Rheum 2006;54:3761–73. 2 Gandjbakhch F, Conaghan PG, Ejbjerg B et al. Synovitis and osteitis are very frequent in rheumatoid arthritis clinical remission: results from an MRI study of 294 patients in clinical remission or low disease activity state. J Rheumatol 2011;38:2039–44. 3 Haavardsholm EA, Boyesen P, Østergaard M et al. Magnetic resonance imaging findings in 84 patients with early rheumatoid arthritis: bone marrow oedema predicts erosive progression. Ann Rheum Dis 2008;67:794–800. 4 Hetland ML, Ejbjerg B, Hørslev-Petersen K et al. MRI bone oedema is the strongest predictor of subsequent radiographic progression in early rheumatoid arthritis. Results from a 2-year randomised controlled trial (CIMESTRA). Ann Rheum Dis 2009;68:384–90. 5 Colebatch AN, Edwards CJ, Ostergaard M et al. EULAR recommendations for the use of imaging of the joints in the clinical management of rheumatoid arthritis. Ann Rheum Dis 2013;72:804–14. 6 Østergaard 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;30:1385–6. 7 Haavardsholm EA, Østergaard M, Ejbjerg BJ et al. Reliability and sensitivity to change of the OMERACT rheumatoid arthritis magnetic resonance imaging score in a multireader, longitudinal setting. Arthritis Rheum 2005; 52:3860–7. 8 Ejbjerg BJ, Vestergaard A, Jacobsen S et al. The smallest detectable difference and sensitivity to change of magnetic resonance imaging and radiographic scoring of structural joint damage in rheumatoid arthritis finger, wrist, and toe joints: a comparison of the OMERACT rheumatoid arthritis magnetic resonance imaging score applied to different joint combinations and the Sharp/van der Heijde radiographic score. Arthritis Rheum 2005;52:2300–6. 9 Schmidt G, Dinter D, Reiser MF et al. The uses and limitations of whole-body magnetic resonance imaging. Dtsch Arztebl Int 2010;107:383–9. 10 Weber U, Hodler J, Jurik AG et al. Assessment of active spinal inflammatory changes in patients with axial spondyloarthritis: validation of whole body MRI against conventional MRI. Ann Rheum Dis 2009;7:7. 11 Weber U, Maksymowych WP, Jurik AG et al. Validation of whole-body against conventional magnetic resonance imaging for scoring acute inflammatory lesions in the sacroiliac joints of patients with spondylarthritis. Arthritis Rheum 2009;61:893–9.

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shown that the scoring of synovitis in peripheral joints from STIR and non-contrast-enhanced T1-weighted images alone is less reliable than the scoring from postcontrast T1-weighted images. However, in the spine and SI joint, inflammation scored from STIR images alone has been shown to be as sensitive and reliable as when scored from T1-weighted post-contrast images [30–33]. WBMRI could potentially be used to provide an imaging joint count (or MRI inflammation count), resulting in a more objective quantification of global inflammation throughout the body. A goal could be to define a standardized global MRI inflammation count, which could be a sensitive method for a more comprehensive evaluation of the inflammatory disease load in RA patients. If only a STIR sequence is used, no contrast agent is needed and an MRI joint count reflecting the overall inflammatory load can be acquired in less than 30 min. However, this requires an improved image quality compared with that in the present study. This study has some limitations. We included only 20 patients, and studies with more patients are needed. The clinical examination did not include examination for tenderness of entheseal sites and it was not possible to compare the WBMRI and clinical findings of enthesitis. Further, we need to perform studies where WBMRI and other imaging modalities, including conventional MRI, are compared. We evaluated the intrareader agreement, but studies with more readers and repeated scans are needed to address the interreader and the interscan agreement. Further, WBMRI follow-up studies are needed to investigate the long-term prognostic utility of WBMRI disease activity with regards to joint destruction, co-morbidities and quality of life in patients with RA. In conclusion, inflammation and structural damage was identified in the peripheral and axial joints and in peripheral entheses by WBMRI and inflammation was more frequently detected by WBMRI than by clinical evaluation. 3T WBMRI is a promising tool for evaluation of overall inflammation and provides a potential option for MRI joint count, including features of inflammation and structural damage, in patients with RA. However, optimization of the imaging protocol and positioning of the hands and feet are needed.

Whole-body MRI in RA

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