Abstract
Objective. Magnetic resonance imaging (MRI) has been increasingly recognized as a critical tool for the assessment of patients with rheumatoid arthritis (RA) and is able to reliably identify synovitis, bone marrow edema, bone erosion, and joint space narrowing (JSN)/cartilage loss. Understanding the exact relationship between each MRI feature and local synovial pathobiology is critical to dissect disease pathogenesis as well as develop future predictive models.
Methods. A systematic review was performed of the current published literature examining the relationship between MRI abnormalities and synovial pathobiology in patients with RA.
Results. Eighteen studies were identified; most focused on validation of MRI as a tool to detect and quantify synovitis, with a significant relationship demonstrated. Additionally, from the limited data available, a critical role seems likely for synovial pathways, at least in driving joint damage. However, there was a lack of data examining the relationship between synovial pathobiology and bone marrow abnormalities and JSN.
Conclusion. Although understanding the interrelationship of these disease biomarkers offers the potential to enhance the predictive validity of modern imaging with concomitant synovial pathobiological analysis, further studies integrating MRI with synovial tissue analysis in well-controlled cohorts at distinct disease stages before and after therapeutic intervention are required to achieve this.
Magnetic resonance imaging (MRI) is an excellent tool to delineate pathology in rheumatoid arthritis (RA) because it can define bone, cartilage, fluid, and soft tissues. This is possible because MRI can delineate structures with high water content on T2-weighted fat-suppressed or short-tau inversion recovery sequences, and following injection of gadolinium-DTPA (Gd-DTPA), regions of high vascularity. Thus, feasibly MRI can quantify both synovial volume and inflammation and act as a surrogate noninvasive marker of histological inflammation. Specific MRI features of RA synovial joints have been demonstrated to be of particular prognostic value: synovitis, bone marrow edema (BME), bone erosions, and cartilage thinning. MRI has the capacity to detect bone erosions 2 years earlier1 than plain radiographs and sensitivity to detect change even in small cohorts2, an effect that is of critical relevance given the capacity of improved treatment algorithms to halt joint damage3. Consequently, MRI is now well recognized as a robust outcome measure in clinical trials.
Historically, the pathological events leading to joint damage in RA have been suggested to be a sequence of primary synovitis leading to BME, cartilage thinning, and finally erosions. There is increasing data to challenge this model. First, although a significant relationship between BME and synovitis4 and between synovitis and the development of bone erosions has been demonstrated5, debate regarding the exact contribution of synovitis/BME in initiating and/or sustaining bone erosion continues6 with some evidence suggesting that BME per se may be an independent predictor of erosive progression4,7,8,9,10,11,12,13. Further, there is evidence primarily from MRI studies to support a bio-mechanical effect on erosive progression14. Second, MRI studies have noted BME and erosions as early events, with cartilage thinning occurring later15. Third, a number of radiographic studies have reported an incongruent relationship between cartilage thinning and erosions15,16. Finally, recent data have demonstrated an association between MRI-documented BME, synovitis, baseline cartilage damage, and subsequent cartilage loss17. These observations raise a number of fundamental questions regarding mechanisms of joint damage and in particular whether synovial pathobiological pathways initiate and/or sustain a local environment that drives BME, erosions, and/or cartilage thinning.
It was within this context that a systematic literature review was conducted to assess published data investigating the relationship between RA synovial pathobiology and MRI BME, synovitis, erosions, and cartilage thinning.
MATERIALS AND METHODS
The study methodology was conducted in line with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines18 and was registered with PROSPERO (www.crd.york.ac.uk/NIHR_PROSPERO, registration CRD42016033875). Because this was a systematic review, no ethics approval was sought, in accordance with the policy of Barts Health NHS Trust.
Search strategy
Relevant articles, reviews, and abstracts were identified through an initial search of EMBASE, MEDLINE, and the Cochrane Library for articles published up to March 2016. The MEDLINE MeSH keyword search terms (rheumatoid arthritis, rheumatoid and arthritis, RA, rheumatoid, inflammatory arthritis, nuclear magnetic resonance imaging, magnetic AND resonance AND imaging, synovitis, synovi, pathology, histopathology, immunohistochemistry, pathol, histo, immune, joint surgery, arthroscopy, biopsy, joints, surgery) and adopted Boolean operators are presented in Table 1. These were modified to accommodate each search database. EMBASE and Cochrane search terms are presented as Supplementary Tables 1 and 2, respectively, available from the authors on request.
The MEDLINE MeSH keyword search terms and Boolean operators from 1946 to present.
Eligibility criteria
Studies including patients with RA undergoing an MRI scan of a peripheral synovial joint along with sampling of synovial tissue were eligible. Outcome measures for MRI scanning included BME, joint erosion, synovitis, and cartilage thickness. Outcome measures for synovial tissue included macro/microscopic histological assessment and immunohistochemical and gene expression analysis. To be included within the review, studies had to directly compare 1 MRI RA feature with 1 or more synovial outcome measures. All types of study designs were included and analysis was restricted to humans. Articles not in English, with no translation available, and abstracts with no corresponding full-text article were excluded.
Two reviewers (FH and AM) independently reviewed the titles and abstracts from potentially relevant articles identified through the search strategy. Both reviewers assessed the full texts of all potentially eligible articles.
Data extraction
Data were entered onto a predefined data extraction table. For each study, the following data were recorded regarding study design: type of study, disease stage (e.g., early vs established disease), procedure for synovial sampling, time interval between synovial sampling and MRI scan, whether concomitant disease-modifying antirheumatic drugs (DMARD) and/or steroid therapy were controlled for, joint imaged, and joint biopsied. The following MRI variables were also recorded: MRI feature scored, acquisition strength, and method of assessment of MRI features. Additionally, the following variables regarding synovial tissue analysis were recorded: number of synovial samples taken, procedure for synovial tissue preparation, macroscopic assessment of synovium, histological assessment of H&E stained samples, immunohistochemical assessment, synovial gene expression analysis, and main conclusions. Data extraction was performed by 1 reviewer (FH) and was verified by a second (AM). Any disagreements regarding data extraction were resolved following discussion among the reviewers.
Quality assessment
The quality of each study was independently assessed by 2 reviewers (FH and AM) using an adapted standardized quality scoring tool (Supplementary Table 3, available from the authors on request)19,20 to assess the following components: (1) study population, (2) MRI assessment and scoring, (3) histological assessment, and (4) study design and analysis and data presentation. A score of “1” or “0” was allocated for each question according to whether the study fulfilled the criteria or not, respectively. A study was considered to be high quality if it exceeded or equaled the mean score (% of total) in its class [cross-sectional vs randomized controlled trial (RCT) vs cohort study].
RESULTS
Search strategy
A summary of the results of the search strategy is presented in the PRISMA flow chart shown in Figure 1. This indicates that a total of 505 articles were identified. Following the exclusion of duplicates (n = 117) and review articles (n = 103), 273 articles were screened. Of these, 237 were excluded (134 because they did not include patients with RA, 91 because they did not include histopathological analysis of synovial tissue, 10 because they were examinations of tissue in vitro or in animal models, and 2 because no MRI scans were included). Of the remaining 36 articles, 18 were then excluded: 2 because no English translation was available, 5 because of no synovial histopathobiological examination (3 had no synovial histology and 2 had synovial explants in vitro only), 1 because there was no comparison of MRI and synovial pathobiology (not relevant to task), 4 because they did not include patients with RA, and 6 because they were abstracts only with no full text (Supplementary Table 5, available from the authors on request). Eighteen articles were then identified that satisfied the eligibility criteria and were therefore included in the review.
PRISMA flow chart presenting the results of the search strategy. PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses; RA: rheumatoid arthritis; MRI: magnetic resonance imaging.
Characteristics of included studies
A summary of the characteristics of the 18 studies is presented in Table 2 (MRI characteristics) and Table 3 (histopathobiological characteristics)21–30,31,32,33,34,35,36,37,38,39. A total of 442 participants were included in the analyses from the 18 studies. Of these, 327 had RA, 19 spondyloarthropathy, 4 psoriatic arthritis, 55 osteoarthritis, 2 healthy controls, and 35 other arthritic conditions. Eleven studies were cross-sectional observational studies21–30,31 and 1 study was a retrospective analysis32. Four studies were prospective open-label clinical trials33,34,35,36, 1 study was a blinded RCT37, and 1 study was a prospective observational clinical study38. Fifteen studies included patients only with established RA (although exact disease duration was not specified in 2 of these studies31,35) and 3 studies specifically included patients with disease duration of < 2 years26,36,38. Fourteen studies sampled synovium from the knee joint and 4 studies included samples from small joints26,31,32,35. Variable methods for synovial sample retrieval were reported: 7 studies using arthroscopy29,31,33,34,36,37,38, 4 arthroplasty21,27,28,32, and 3 using both22,23,30. Two studies used blind needle biopsy24,25 and 2 miniarthroscopy (Table 2)26,35. Acquisition of images was performed on a 1.5T MRI scanner with contrast administration in 13 studies21,22,23,26,27,28,29,30,32,33,34,36,37 and without in 1 study38. Two studies used a 0.5T + contrast administration24,25 and 2 a 3T+ contrast protocol31,35, although the latter study used a 0.2T scanner in a significant proportion of patients (4/10) with claustrophobia (Table 2).
Summary of studies directly correlating MRI features with synovial pathobiology: MRI characteristics.
Summary of studies directly correlating MRI features with synovial pathobiology: histobiological characteristics.
Quality assessment of studies
A summary of quality scoring of studies is provided in supplementary data (Supplementary Table 4, available from the authors on request). Quality scores were converted to percentages of the maximum score within each class of study. The mean (range) quality score