Curr Rheumatol Rep (2014) 16:388 DOI 10.1007/s11926-013-0388-1
IMAGING (P CONAGHAN, SECTION EDITOR)
Insights into Rheumatoid Arthritis from Use of MRI Fiona M. McQueen & Estee Chan
Published online: 17 November 2013 # Springer Science+Business Media New York 2013
Abstract Magnetic resonance imaging (MRI) is ideal for imaging the joints of rheumatoid arthritis (RA) patients. It produces anatomically detailed images of bone, cartilage, tendons and synovial membrane. It can reveal structural damage, in the form of bone erosion, cartilage thinning and/or tendon rupture, and regions of inflammation, using sequences that reveal water content and vascularity. MRI synovitis, tenosynovitis and bone oedema/ osteitis all have prognostic significance, and MRI studies of RA have helped elucidate the mechanisms whereby bone and synovial inflammation lead to joint damage. Bone oedema/osteitis has become an important imaging biomarker, and can be used to help predict progression from undifferentiated arthritis to definite RA. Recent MRI studies have confirmed that subclinical inflammation is often present in patients in clinical remission, and these data may affect disease management. Finally, recent clinical trials are reviewed, in which MRI outcome measures are being established as sensitive response markers. Keywords Rheumatoid arthritis . MRI . Imaging . Erosions . Cartilage . Synovitis . Osteitis . Bone oedema . Tenosynovitis . Clinical trials
This article is part of the Topical Collection on Imaging F. M. McQueen (*) Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Rd, Grafton, Auckland, New Zealand e-mail: [email protected] F. M. McQueen : E. Chan Department of Rheumatology, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand
Introduction Over the last decade, MRI scanning has provided several insights into the development and progression of joint inflammation and damage in rheumatoid arthritis (RA), and has helped shape concepts of disease pathogenesis. This imaging modality possesses several unique attributes that make it particularly useful for investigating the rheumatoid joint. These include: first, its three-dimensionality, which means that anatomically complex regions, for example the wrist, can be imaged without difficulty, particularly when compared with two-dimensional plain radiography (XR) which produces images that may be difficult to interpret because of overlapping bony contours [1]. Second, MRI can image all body regions; this is in contrast with, for example, ultrasound (US), which cannot access some areas of the wrist, tarsus and metacarpophalangeal (MCP) joints [2]. Third, MRI can image damage and inflammation simultaneously, with a high degree of clarity, especially using advanced high-field systems with an excellent signal-to-noise ratio [3]. Features indicating damage within the rheumatoid joint include bone erosion, cartilage thinning and tendon rupture with associated malalignment. Multiple studies have revealed that bone erosion can be detected by use of MRI well before it is apparent on XR [4, 5]. MRI can be used to detect cartilage thinning at the large joints, for example the knee, and recent advances in scan technology have enabled better imaging of cartilage change at the small joints of the hand and wrist [6]. Thinning and rupture of tendons can also be assessed and quantified by use of this modality [7]. Joint inflammation is traditionally regarded by rheumatologists as primarily involving the synovium and tenosynovium, but more recently the MRI “bone oedema” lesion was found to indicate bone inflammation or osteitis [8], with significance for disease pathogenesis and prognosis. Finally, MRI is an optimum modality for following the progression of inflammation and damage
388, Page 2 of 11
over time: it is digitised, so that scan data can be stored and retrieved, and it does not involve exposure of the patient to ionising radiation. Figure 1 shows typical features of bone erosion, bone oedema/osteitis and synovitis in the rheumatoid wrist of a 60-year-old woman with disease duration of five years, who was noncompliant with all medication. These indicators of joint inflammation and damage are now routinely assessed by use of the rheumatoid arthritis MRI scoring system (RAMRIS) [9], developed by a multinational group under the auspices of the outcomes measures in rheumatoid arthritis clinical trials (OMERACT) MRI working group. In this article we will summarise recent advances in the understanding of rheumatoid pathology, inspired and developed by insights from MRI data. We will also summarise the use of MRI outcome measures in the clinical trial setting, and the rapidly expanding clinical role of MRI in diagnosing and monitoring disease and defining remission.
Quantitative MRI Techniques RAMRIS [9] is a semi-quantitative MRI scoring method that has been widely adopted for assessing RA joint inflammation and damage, and is increasingly being used as a measurement tool for assessing efficacy of biological disease-suppressing drugs (bDMARDs) in clinical trials [10]. Using the RAMRIS system, erosions are scored 1–10 on the basis of estimated bone volume loss, bone oedema/osteitis is graded 0–3 on the basis of volume of involved bone, and synovitis is assigned a 0–3 score for severity as indicated by synovial thickness and post-contrast enhancement. An atlas depicting typical lesions Fig. 1 3 T MRI scans of the wrist of a 60-year-old Indian woman with rheumatoid arthritis of five years’ duration, who was non-compliant with all DMARD medication. (a) T1w coronal image shows an erosion within the scaphoid (arrow) and bone oedema/osteitis within the lunate (circle). (b) T1w FS postcontrast coronal image showing bright signal within the erosion (arrow) and the lunate bone oedema/osteitis lesion (circle). (c) T1w axial image confirms erosion breaching the cortex within the scaphoid (arrow). (d) T1w FS post-contrast shows bright signal within the erosion and surrounding bone oedema/osteitis (arrow). There is also enhancement within the intercarpal joint, indicating synovitis (arrowheads)
Curr Rheumatol Rep (2014) 16:388
for each score is available, and can be used as a standard against which MRI findings can be compared [11]. Haavardsholm et al. have suggested the addition of a tenosynovitis score along similar lines [12], and recently two separate groups have devised systems for using MRI to assign a score to cartilage damage at the wrist [13, 14]. RAMRIS has been well validated, with high levels of interreader reliability and sensitivity to change [15]. However, computer-assisted techniques now exist that may be used to quantify erosion more directly, with the potential to detect more subtle damage progression than can be measured by use of a graded score. This has already been achieved for plain radiography; computer-assisted X-ray measurements were found by one study to be more sensitive than radiographs scored according to traditional methods for detecting RA erosion progression [16]. Recently, Poh et al. investigated computer-assisted measurement of MRI bone erosion volume in RA and reported that reliability was superior to RAMRIS, with an inter-reader intra-class correlation coefficient (ICC) of 0.85 (0.53–0.96) [17]. The standardised response mean was also high at 0.63 (indicating good responsiveness for detecting change), compared with 0.58 for RAMRIS and 0.39 for the Xray Sharp erosion score. Computer-assisted volume measurements identified 10 of 32 patients who progressed over the course of two years, whereas RAMRIS identified only four of these. A separate cross-sectional study [18] also compared computer-assisted quantitation with RAMRIS and revealed comparable reliability for determining erosion volume but not for assessing the bone oedema/osteitis lesion for which RAMRIS scoring was superior. This may reflect difficulty using the computer mouse to delineate the borders of the bone
Curr Rheumatol Rep (2014) 16:388
oedema/osteitis lesion, which are typically “feathery” and illdefined. Another study examined the reliability, validity and feasibility of a computer-assisted segmentation method for determining synovial membrane volume as a surrogate measure of synovitis in RA [19, 20]. The technique had very good reliability and validity (synovial volumes correlated strongly with RAMRIS synovitis scores), but feasibility was only moderate because the segmentation technique took approximately 20 min per patient. Boesen et al. recently compared manual and computer-aided techniques for evaluating wrist synovitis on dynamic contrast-enhanced MRI scans [21]. Their semi-automated model-based approach generated reproducible results when they used motion-reduction algorithms to improve the signal-to-noise ratio. This field is developing rapidly and with advances in technology it is probable that computer software will increasingly be used to improve the accuracy of MRI assessment of rheumatoid disease activity and damage.
MRI Insights into the Pathogenesis of RA Inflammation—Bone Oedema/Osteitis The traditional view of RA pathogenesis holds that the dominant site of inflammation is the synovial membrane which invests the joint and/or adjacent tendons and bursae, and that this tissue is directly responsible for damage to underlying cartilage and bone. This hypothesis was supported by studies including those of Pap et al., who confirmed invasion of RA fibroblast-like synoviocytes (FLS) into cartilage implants in the subacute combined immunodeficiency (SCID) mouse RA model [22]. Proinflammatory cytokines released within the synovial membrane were also implicated in activating enzymes, including matrix metalloproteinases (MMPs), capable of directly lysing cartilage and bone and potentially leading to the formation of erosions by “burrowing down” through the joint surface into the subchondral bone [23]. MRI findings have increased the scope of RA research in a number of ways, revealing that the bone beneath the joint is not an “inert scaffold” but rather another major site of inflammation [24]. In 2003, McQueen et al. were the first to report that the bone oedema lesion was a major predictor of subsequent bone erosion, using MRI scan data from a cohort of early RA patients studied over a six-year period [25]. Interestingly, MRI synovitis predicted erosion after one-year follow-up [26] but had lost significance as an individual predictor of erosion on multivariate analysis after six years [25]. This was also reported in 2009 by Mundwiler et al., studying the metatarsophalangeal (MTP) joints of the feet [27]. They did not find an association between synovitis and later erosive damage at individual joints, but reported that bone oedema was a predictor of bone erosion. Meanwhile,
Page 3 of 11, 388
other large cohort studies from Norway [28] and Denmark [29] confirmed these findings. In the Danish study, Hetland et al. revealed that bone oedema was the strongest predictor of erosion, and was superior to all other clinical and immunological measures assessed (including anti-cyclic citrillunated peptide antibody (anti-CCP) status) for predicting later erosive disease [28, 30]. Subsequently these groups and others worked to incorporate MRI outcome measures into clinical trials, and this application is discussed in more detail below and in Table 1. In 2007, groups from the United States and New Zealand, working separately, managed to obtain bone from rheumatoid joints resected during joint arthroplasty and confirmed that the bone oedema lesion equated to histological osteitis [31, 32], which was later characterised as being a lymphoplasmacytic inflammatory infiltrate within trabecular bone [33]. Immunostaining confirmed receptor activator of nuclear factor kappa-B ligand (RANKL) expression, suggesting a pathway whereby tumour necrosis factor alpha (TNFα)mediated osteoclast activation could be facilitated [34] and bone be eroded “from the inside out” as proposed by Schett et al. [23]. Over the last five years, reports of MRI studies have continued to reinforce the theory that bone oedema/osteitis is important as a prognostic factor for aggressive erosive RA. In a French study of 85 patients [35•] this marker predicted structural progression (erosion) over one year, even for patients with low disease activity. This study used low-field MRI scanning (0.2 T), which is important because that modality has been revealed to be less sensitive for the detection of bone oedema than high field MRI [36], suggesting the effect could have been underestimated. Boyesen et al., reporting on a cohort of 50 patients, found both baseline and one-year cumulative measures of MRI synovitis and bone marrow oedema independently predicted three-year radiographic progression [37]. Many studies now combine bone oedema/osteitis and synovitis as an overall marker of joint inflammation [38]. Inflammation—pre-RA Recent work has suggested that both MRI synovitis and bone oedema/osteitis are present in patients with “pre-RA”: a group who have arthralgia and who are positive for anti-cyclic citrullinated peptide antibodies (ACPA), but do not yet meet American College of Rheumatology (ACR) criteria [39]. Krabben et al. studied 21 pre-RA patients and compared them with established RA patients and healthy controls by use of 1.5 T MRI imaging. The mean combined inflammation scores (incorporating synovitis and bone oedema/osteitis) of painful joints within the hands, wrists and forefeet, were highest for criteria-positive RA patients, but scores for pre-RA patients were higher than the scores of healthy controls. At the MCP joints, the combined inflammation score correlated with levels of inflammatory markers, including C-reactive protein (CRP)
Non-MRI imaging outcome measures
MRI results
1.5 T MRI + contrast at 0 and 219 patients, >12 months duration. 3 months. One hand and Active disease at enrolment, SJC wrist joint, synovitis, osteitis ≥6, TJC ≥6, and at least one of: and erosion using RAMRIS. ESR>ULN or CRP >8.0 mg L−1, + failure to respond to one biological agent.
1.5 T MRI + contrast at 0, 12, 240 patients, >3 months duration. 24, 52 and 104 weeks. Active disease at enrolment Dominant wrist and MCP despite MTX, SJC ≥4, TJC ≥4, joints for synovitis, osteitis and at least two of: CRP ≥1.5 mg and erosion using RAMRIS. dl−1 or ESR ≥28 mm h−1, EMS ≥30 min, bone erosion by XR or MRI, or RF/anti-CCP + ve
1.5 T MRI + contrast at 0, 12, 318 patients, >3 months duration, 24, 52 and 104 weeks. MTX naïve. Active disease at Dominant wrist and MCP enrolment, SJC ≥4, TJC ≥4, and joints for synovitis, osteitis at least two of: CRP ≥1.5 mg dl−1 or ESR ≥28 mm h−1, morning and erosion using RAMRIS. stiffness ≥30 min, bone erosion by XR or MRI, or RF or antiCCP positivity.
Conaghan et al. 2011 GO-FORWARD MRI [61] substudy, placebo/MTX (group 1) vs. golimumab 100 mg/placebo (group 2) vs. golimumab 50 mg/MTX (group 3) vs. golimumab 100 mg/MTX (group 4), for 24 weeks.
Ostergaard et al. 2011 GO-BEFORE study, placebo/ [77••] MTX (group 1) vs. golimumab 100 mg/placebo (group 2) vs. golimumab 50 mg/MTX (group 3) vs. golimumab 100 mg/MTX (group 4), for 52 weeks.
0.6T MRI + contrast at 0, 6 and 12 months. Index wrist and 2nd–5th MCP joint synovitis, osteitis and erosion using RAMRIS.
CT index wrist and MCP 2nd– Mean change in synovitis=−1.2 5th at 0, 6 and 12 months. (p
IMAGING (P CONAGHAN, SECTION EDITOR)
Insights into Rheumatoid Arthritis from Use of MRI Fiona M. McQueen & Estee Chan
Published online: 17 November 2013 # Springer Science+Business Media New York 2013
Abstract Magnetic resonance imaging (MRI) is ideal for imaging the joints of rheumatoid arthritis (RA) patients. It produces anatomically detailed images of bone, cartilage, tendons and synovial membrane. It can reveal structural damage, in the form of bone erosion, cartilage thinning and/or tendon rupture, and regions of inflammation, using sequences that reveal water content and vascularity. MRI synovitis, tenosynovitis and bone oedema/ osteitis all have prognostic significance, and MRI studies of RA have helped elucidate the mechanisms whereby bone and synovial inflammation lead to joint damage. Bone oedema/osteitis has become an important imaging biomarker, and can be used to help predict progression from undifferentiated arthritis to definite RA. Recent MRI studies have confirmed that subclinical inflammation is often present in patients in clinical remission, and these data may affect disease management. Finally, recent clinical trials are reviewed, in which MRI outcome measures are being established as sensitive response markers. Keywords Rheumatoid arthritis . MRI . Imaging . Erosions . Cartilage . Synovitis . Osteitis . Bone oedema . Tenosynovitis . Clinical trials
This article is part of the Topical Collection on Imaging F. M. McQueen (*) Department of Molecular Medicine and Pathology, Faculty of Medical and Health Sciences, University of Auckland, 85 Park Rd, Grafton, Auckland, New Zealand e-mail: [email protected] F. M. McQueen : E. Chan Department of Rheumatology, Greenlane Clinical Centre, Auckland District Health Board, Auckland, New Zealand
Introduction Over the last decade, MRI scanning has provided several insights into the development and progression of joint inflammation and damage in rheumatoid arthritis (RA), and has helped shape concepts of disease pathogenesis. This imaging modality possesses several unique attributes that make it particularly useful for investigating the rheumatoid joint. These include: first, its three-dimensionality, which means that anatomically complex regions, for example the wrist, can be imaged without difficulty, particularly when compared with two-dimensional plain radiography (XR) which produces images that may be difficult to interpret because of overlapping bony contours [1]. Second, MRI can image all body regions; this is in contrast with, for example, ultrasound (US), which cannot access some areas of the wrist, tarsus and metacarpophalangeal (MCP) joints [2]. Third, MRI can image damage and inflammation simultaneously, with a high degree of clarity, especially using advanced high-field systems with an excellent signal-to-noise ratio [3]. Features indicating damage within the rheumatoid joint include bone erosion, cartilage thinning and tendon rupture with associated malalignment. Multiple studies have revealed that bone erosion can be detected by use of MRI well before it is apparent on XR [4, 5]. MRI can be used to detect cartilage thinning at the large joints, for example the knee, and recent advances in scan technology have enabled better imaging of cartilage change at the small joints of the hand and wrist [6]. Thinning and rupture of tendons can also be assessed and quantified by use of this modality [7]. Joint inflammation is traditionally regarded by rheumatologists as primarily involving the synovium and tenosynovium, but more recently the MRI “bone oedema” lesion was found to indicate bone inflammation or osteitis [8], with significance for disease pathogenesis and prognosis. Finally, MRI is an optimum modality for following the progression of inflammation and damage
388, Page 2 of 11
over time: it is digitised, so that scan data can be stored and retrieved, and it does not involve exposure of the patient to ionising radiation. Figure 1 shows typical features of bone erosion, bone oedema/osteitis and synovitis in the rheumatoid wrist of a 60-year-old woman with disease duration of five years, who was noncompliant with all medication. These indicators of joint inflammation and damage are now routinely assessed by use of the rheumatoid arthritis MRI scoring system (RAMRIS) [9], developed by a multinational group under the auspices of the outcomes measures in rheumatoid arthritis clinical trials (OMERACT) MRI working group. In this article we will summarise recent advances in the understanding of rheumatoid pathology, inspired and developed by insights from MRI data. We will also summarise the use of MRI outcome measures in the clinical trial setting, and the rapidly expanding clinical role of MRI in diagnosing and monitoring disease and defining remission.
Quantitative MRI Techniques RAMRIS [9] is a semi-quantitative MRI scoring method that has been widely adopted for assessing RA joint inflammation and damage, and is increasingly being used as a measurement tool for assessing efficacy of biological disease-suppressing drugs (bDMARDs) in clinical trials [10]. Using the RAMRIS system, erosions are scored 1–10 on the basis of estimated bone volume loss, bone oedema/osteitis is graded 0–3 on the basis of volume of involved bone, and synovitis is assigned a 0–3 score for severity as indicated by synovial thickness and post-contrast enhancement. An atlas depicting typical lesions Fig. 1 3 T MRI scans of the wrist of a 60-year-old Indian woman with rheumatoid arthritis of five years’ duration, who was non-compliant with all DMARD medication. (a) T1w coronal image shows an erosion within the scaphoid (arrow) and bone oedema/osteitis within the lunate (circle). (b) T1w FS postcontrast coronal image showing bright signal within the erosion (arrow) and the lunate bone oedema/osteitis lesion (circle). (c) T1w axial image confirms erosion breaching the cortex within the scaphoid (arrow). (d) T1w FS post-contrast shows bright signal within the erosion and surrounding bone oedema/osteitis (arrow). There is also enhancement within the intercarpal joint, indicating synovitis (arrowheads)
Curr Rheumatol Rep (2014) 16:388
for each score is available, and can be used as a standard against which MRI findings can be compared [11]. Haavardsholm et al. have suggested the addition of a tenosynovitis score along similar lines [12], and recently two separate groups have devised systems for using MRI to assign a score to cartilage damage at the wrist [13, 14]. RAMRIS has been well validated, with high levels of interreader reliability and sensitivity to change [15]. However, computer-assisted techniques now exist that may be used to quantify erosion more directly, with the potential to detect more subtle damage progression than can be measured by use of a graded score. This has already been achieved for plain radiography; computer-assisted X-ray measurements were found by one study to be more sensitive than radiographs scored according to traditional methods for detecting RA erosion progression [16]. Recently, Poh et al. investigated computer-assisted measurement of MRI bone erosion volume in RA and reported that reliability was superior to RAMRIS, with an inter-reader intra-class correlation coefficient (ICC) of 0.85 (0.53–0.96) [17]. The standardised response mean was also high at 0.63 (indicating good responsiveness for detecting change), compared with 0.58 for RAMRIS and 0.39 for the Xray Sharp erosion score. Computer-assisted volume measurements identified 10 of 32 patients who progressed over the course of two years, whereas RAMRIS identified only four of these. A separate cross-sectional study [18] also compared computer-assisted quantitation with RAMRIS and revealed comparable reliability for determining erosion volume but not for assessing the bone oedema/osteitis lesion for which RAMRIS scoring was superior. This may reflect difficulty using the computer mouse to delineate the borders of the bone
Curr Rheumatol Rep (2014) 16:388
oedema/osteitis lesion, which are typically “feathery” and illdefined. Another study examined the reliability, validity and feasibility of a computer-assisted segmentation method for determining synovial membrane volume as a surrogate measure of synovitis in RA [19, 20]. The technique had very good reliability and validity (synovial volumes correlated strongly with RAMRIS synovitis scores), but feasibility was only moderate because the segmentation technique took approximately 20 min per patient. Boesen et al. recently compared manual and computer-aided techniques for evaluating wrist synovitis on dynamic contrast-enhanced MRI scans [21]. Their semi-automated model-based approach generated reproducible results when they used motion-reduction algorithms to improve the signal-to-noise ratio. This field is developing rapidly and with advances in technology it is probable that computer software will increasingly be used to improve the accuracy of MRI assessment of rheumatoid disease activity and damage.
MRI Insights into the Pathogenesis of RA Inflammation—Bone Oedema/Osteitis The traditional view of RA pathogenesis holds that the dominant site of inflammation is the synovial membrane which invests the joint and/or adjacent tendons and bursae, and that this tissue is directly responsible for damage to underlying cartilage and bone. This hypothesis was supported by studies including those of Pap et al., who confirmed invasion of RA fibroblast-like synoviocytes (FLS) into cartilage implants in the subacute combined immunodeficiency (SCID) mouse RA model [22]. Proinflammatory cytokines released within the synovial membrane were also implicated in activating enzymes, including matrix metalloproteinases (MMPs), capable of directly lysing cartilage and bone and potentially leading to the formation of erosions by “burrowing down” through the joint surface into the subchondral bone [23]. MRI findings have increased the scope of RA research in a number of ways, revealing that the bone beneath the joint is not an “inert scaffold” but rather another major site of inflammation [24]. In 2003, McQueen et al. were the first to report that the bone oedema lesion was a major predictor of subsequent bone erosion, using MRI scan data from a cohort of early RA patients studied over a six-year period [25]. Interestingly, MRI synovitis predicted erosion after one-year follow-up [26] but had lost significance as an individual predictor of erosion on multivariate analysis after six years [25]. This was also reported in 2009 by Mundwiler et al., studying the metatarsophalangeal (MTP) joints of the feet [27]. They did not find an association between synovitis and later erosive damage at individual joints, but reported that bone oedema was a predictor of bone erosion. Meanwhile,
Page 3 of 11, 388
other large cohort studies from Norway [28] and Denmark [29] confirmed these findings. In the Danish study, Hetland et al. revealed that bone oedema was the strongest predictor of erosion, and was superior to all other clinical and immunological measures assessed (including anti-cyclic citrillunated peptide antibody (anti-CCP) status) for predicting later erosive disease [28, 30]. Subsequently these groups and others worked to incorporate MRI outcome measures into clinical trials, and this application is discussed in more detail below and in Table 1. In 2007, groups from the United States and New Zealand, working separately, managed to obtain bone from rheumatoid joints resected during joint arthroplasty and confirmed that the bone oedema lesion equated to histological osteitis [31, 32], which was later characterised as being a lymphoplasmacytic inflammatory infiltrate within trabecular bone [33]. Immunostaining confirmed receptor activator of nuclear factor kappa-B ligand (RANKL) expression, suggesting a pathway whereby tumour necrosis factor alpha (TNFα)mediated osteoclast activation could be facilitated [34] and bone be eroded “from the inside out” as proposed by Schett et al. [23]. Over the last five years, reports of MRI studies have continued to reinforce the theory that bone oedema/osteitis is important as a prognostic factor for aggressive erosive RA. In a French study of 85 patients [35•] this marker predicted structural progression (erosion) over one year, even for patients with low disease activity. This study used low-field MRI scanning (0.2 T), which is important because that modality has been revealed to be less sensitive for the detection of bone oedema than high field MRI [36], suggesting the effect could have been underestimated. Boyesen et al., reporting on a cohort of 50 patients, found both baseline and one-year cumulative measures of MRI synovitis and bone marrow oedema independently predicted three-year radiographic progression [37]. Many studies now combine bone oedema/osteitis and synovitis as an overall marker of joint inflammation [38]. Inflammation—pre-RA Recent work has suggested that both MRI synovitis and bone oedema/osteitis are present in patients with “pre-RA”: a group who have arthralgia and who are positive for anti-cyclic citrullinated peptide antibodies (ACPA), but do not yet meet American College of Rheumatology (ACR) criteria [39]. Krabben et al. studied 21 pre-RA patients and compared them with established RA patients and healthy controls by use of 1.5 T MRI imaging. The mean combined inflammation scores (incorporating synovitis and bone oedema/osteitis) of painful joints within the hands, wrists and forefeet, were highest for criteria-positive RA patients, but scores for pre-RA patients were higher than the scores of healthy controls. At the MCP joints, the combined inflammation score correlated with levels of inflammatory markers, including C-reactive protein (CRP)
Non-MRI imaging outcome measures
MRI results
1.5 T MRI + contrast at 0 and 219 patients, >12 months duration. 3 months. One hand and Active disease at enrolment, SJC wrist joint, synovitis, osteitis ≥6, TJC ≥6, and at least one of: and erosion using RAMRIS. ESR>ULN or CRP >8.0 mg L−1, + failure to respond to one biological agent.
1.5 T MRI + contrast at 0, 12, 240 patients, >3 months duration. 24, 52 and 104 weeks. Active disease at enrolment Dominant wrist and MCP despite MTX, SJC ≥4, TJC ≥4, joints for synovitis, osteitis and at least two of: CRP ≥1.5 mg and erosion using RAMRIS. dl−1 or ESR ≥28 mm h−1, EMS ≥30 min, bone erosion by XR or MRI, or RF/anti-CCP + ve
1.5 T MRI + contrast at 0, 12, 318 patients, >3 months duration, 24, 52 and 104 weeks. MTX naïve. Active disease at Dominant wrist and MCP enrolment, SJC ≥4, TJC ≥4, and joints for synovitis, osteitis at least two of: CRP ≥1.5 mg dl−1 or ESR ≥28 mm h−1, morning and erosion using RAMRIS. stiffness ≥30 min, bone erosion by XR or MRI, or RF or antiCCP positivity.
Conaghan et al. 2011 GO-FORWARD MRI [61] substudy, placebo/MTX (group 1) vs. golimumab 100 mg/placebo (group 2) vs. golimumab 50 mg/MTX (group 3) vs. golimumab 100 mg/MTX (group 4), for 24 weeks.
Ostergaard et al. 2011 GO-BEFORE study, placebo/ [77••] MTX (group 1) vs. golimumab 100 mg/placebo (group 2) vs. golimumab 50 mg/MTX (group 3) vs. golimumab 100 mg/MTX (group 4), for 52 weeks.
0.6T MRI + contrast at 0, 6 and 12 months. Index wrist and 2nd–5th MCP joint synovitis, osteitis and erosion using RAMRIS.
CT index wrist and MCP 2nd– Mean change in synovitis=−1.2 5th at 0, 6 and 12 months. (p
