Juvenile Idiopathic Arthritis of the Axial Joints: A Systematic Review of the Diagnostic Accuracy and Predictive Value of Conventional MRI

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1 Pediatric Imaging Review Munir et al. MRI for Diagnosis of JIA in the Axial Joints Pediatric Imaging Review Sohaib Munir 1 Kedar Patil 2 Elka Miller 3 Elizabeth Uleryk 3 Marinka Twilt 3 Lynn Spiegel 3 Andrea S. Doria 3 Munir S, Patil K, Miller E, et al. Keywords: axial skeleton, children, evidence-based imaging, juvenile idiopathic arthritis, sacroiliac joint, spine, temporomandibular joint DOI: /AJR Received December 10, 2012; accepted after revision April 29, Faculty of Health Sciences, Queen s University, Kingston, ON, Canada. 2 Department of Diagnostic Radiology, McGill University, Montreal, QC, Canada. 3 Department of Diagnostic Imaging, The Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON M5G 1X8, Canada. Address correspondence to A. S. Doria (andrea.doria@sickkids.ca). AJR 2014; 202: X/14/ American Roentgen Ray Society Juvenile Idiopathic Arthritis of the Axial Joints: A Systematic Review of the Diagnostic Accuracy and Predictive Value of Conventional MRI OBJECTIVE. Our objective was to evaluate the diagnostic accuracy and reliability of MRI and its ability to depict responsiveness to treatment for the evaluation of the axial joints (temporomandibular joint [TMJ], spinal joints, and sacroiliac joints) in juvenile idiopathic arthritis (JIA). CONCLUSION. There is fair (grade B) evidence that MRI is an accurate diagnostic method for evaluating early and intermediate changes in the TMJ in JIA and insufficient evidence to indicate MRI is an accurate diagnostic method for detecting JIA in the spinal (grade I) and sacroiliac (grade I) joints. J uvenile idiopathic arthritis (JIA) is the most common chronic musculoskeletal disease of childhood; the prevalence of JIA ranges between 0.07 and 4.01 per 1000 children and varies on the basis of ethnicity and geography [1]. The precise pathogenic mechanism of JIA is currently unknown; however, it is believed to involve an autoimmune process, beginning with synovial hypertrophy and subsequently affecting the articular cartilage and subchondral bone [1]. Although JIA may be transient and self-limiting, approximately 10% of affected children remain severely disabled in adulthood [2 4]. The ultimate outcome of progression of disease is changes in joint function [5]. The rate of temporomandibular joint (TMJ) involvement in patients with JIA varies from 17% to 87% [6 8] depending on the method of examination applied and the population investigated. Involvement of the TMJ in JIA often occurs without clinically detectable signs and symptoms, therefore delaying the diagnosis [2]. By the time lower jaw asymmetry or retrognathism can be detected clinically, irreversible condylar damage is already established [9, 10]. To prevent irreversible structural JIA complications, early diagnosis and effective treatment of TMJ arthritis [11] are needed. Thus, for the purpose of early diagnosis, an accurate diagnostic test besides physical examination is imperative. Radiography, because of its limitations, is nonspecific for the diagnosis of early JIA changes and cannot always detect early and subtle joint abnormalities in JIA. Conversely, MRI is the diagnostic imaging modality of choice for analysis of joints in patients with JIA [12], allowing assessment of the morphologic status of the joints at a given time point for assessment of early changes in soft tissues and articular cartilage and for evaluation of disease progression [13]. The overall high diagnostic accuracy of MRI for the assessment of JIA in the peripheral joints [14] makes it an appealing resource for early diagnosis, characterization, and follow-up assessment of TMJ. Nevertheless, to our knowledge, no previous systematic review has graded the level of evidence of studies to assess the ability of MRI for determining the diagnosis and prognosis of JIA in axial joints. Summarizing the information in the literature in light of evidence-based imaging tools and identifying gaps in the literature are paramount to determine the status of knowledge and guide future research directions in the field. We applied the Standards for Reporting of Diagnostic Accuracy (STARD) [15] to determine the quality of reporting of selected studies and the level of evidence of MRI examinations of JIA in the axial skeletal joints according to the Canadian Task Force on Preventive Health Care guidelines [16]. Last, we identified gaps in the literature based on a priori designed overarching questions that require further research to improve the effectiveness of clinical applications of MRI and to improve medical management of JIA in the future. AJR:202, January

2 Munir et al. Diagnostic accuracy: validity (items 1, 2, 4, and 5), reliability (items 1 and 2), responsiveness (item 3) Persons at risk JIA patients 0 18 years old Screening not applicable Fig. 1 Analytic framework for use of MRI as diagnostic tool for detection of axial skeleton abnormalities in juvenile idiopathic arthritis (JIA). Dashed lines indicate gaps in literature. Items 1 5 represent overarching questions of review. With regard to clinimetric properties of MRI assessed in primary studies, items 1, 2, 4, and 5 related to construct or criterion validity of MRI in relation to clinical or laboratory constructs or to reference standard, respectively; items 1 and 2, to reliability of MRI interpretation by readers; and item 3, to ability of MRI to detect joint changes over specific intervals of time. JIA = juvenile idiopathic arthritis, TMJ = temporomandibular joint, CHAQ = Childhood Health Assessment Questionnaire. Materials and Methods Overarching Questions This study assessed whether there is evidence that the currently available MRI techniques are accurate for early diagnosis and whether they improve the assessment of the functional status of joints at a single time point and over time in axial skeleton joints of children with JIA. An analytic framework (Fig. 1) was developed before the commencement of this study to facilitate our understanding of the interrelationship of overarching questions in the context of the proposed systematic review and the perception of gaps in the literature in various diagnostic accuracy methodologic aspects. We investigated different bodies of evidence related to the following five overarching questions: question 1, Can MRI be used to detect early axial joint changes?; question 2, Can MRI be used to detect intermediate and late axial joint changes with regard to the progression of arthropathy?; question 3, Is MRI useful to monitor the effect of treatment on improving joint Detection of early joint changes using MRI In TMJ: Synovial hypertrophy (pannus) Synovial enhancement (synovitis) Joint effusion In spinal joints: Synovial hypertrophy (pannus) Synovial enhancement (synovitis) Inflammation around ligaments Mild disk space narrowing In sacroiliac joints: Bone marrow edema Joint enhancement Mild joint space widening MRI assessment of treatment effect 4 Detection of intermediate and late joint changes using MRI In TMJ: Abnormalities in mandibular condyle and disk morphology Erosions Subchondral cyst abnormalities In spinal joints: Decreased joint space Erosions Atlantoaxial subluxation (in cervical spine) In sacroiliac joints: Widened joint space Erosions Predictive ability 4 Predictive ability pathology and preventing further damage?; question 4, If early changes can be evaluated using MRI, can this information be used to predict future cartilage degeneration or the functional status of the joint?; and question 5, Can an association be made between intermediate and late findings on MRI and the functional status of the joint? Data Sources and Search An electronic literature search was independently conducted by four reviewers who identified studies pertaining to the diagnostic accuracy of MRI in the assessment of the axial skeleton (i.e., TMJ, sacroiliac joints, and spinal joints) of children with JIA. The MEDLINE database (January 1946 June 2012), EMBASE database (January 1980 June 2012), Database of Abstracts of Reviews of Effects (DARE) of the National Health Service Centre for Reviews and Dissemination, and Cochrane Library database were searched through OvidSP (Wolters Kluwer) using an optimal search strategy. The Reduced morbidity, mortality, or both Association Better functional status of joints (CHAQ scores) search combined medical subject headings and EM- BASE terms with free text words. The search terms included juvenile idiopathic arthritis, juvenile rheumatoid arthritis, arthritis, cartilage degeneration, magnetic resonance imaging, activities of daily living, temporomandibular, diagnostic sensitivity, treatment, and outcome. Manual identification of relevant articles by referring to reference lists of selected articles was also conducted. Study Identification Three reviewers independently assessed the titles and keywords of all included citations to determine which were ineligible based on the inclusion criteria. When the content was not clear from the title or keywords, the abstracts were retrieved and assessed. All included abstracts were further evaluated using the inclusion criteria. All original articles of the selected studies were assessed in entirety and ineligible studies were eliminated. Finally, all remaining studies written in English were reviewed independently. At any AJR:202, January 2014

3 MRI for Diagnosis of JIA in the Axial Joints TABLE 1: Demographic and Clinimetric Properties, Semiquantitative and Qualitative Assessments of Quality Using Standards for Reporting of Diagnostic Accuracy (STARD) Scores, and Level of Evidence of Selected Studies Reference No. (Year) No. of Patients With JIA No. and Types of Joints Examined Age (y) Sex Ratio (M:F) STARD Score Level of Evidence Research Design Qual Semi PI b EI c DI d Construct Validity a Criterion Validity e of Other Constructs Against MRI Reliability f Resp g [35] (1993) TMJ 10.4 (mean) 4: Poor II-3 Unclear Y [36] (1996) 20 CS joints of 20 patients 10 (mean) 13: Poor II-3 Unclear Y [20] (1998) 87 SI, numbers unclear 13.1 (mean) 52: Fair II-2 P Y [21] (1998) 60 SI, numbers unclear 13.4 (mean) 37: Fair II-2 P Y [7] (1998) TMJ 12 (mean) NR 0.67 Fair II-2 P Y [22] (2005) 23 TMJ, numbers unclear 9 (median) 3: Fair II-2 R Y Y Y [23] (2005) TMJ h 12 (mean) NR 0.73 Fair II-2 P Y [24] (2007) TMJ 8.3 (mean) 1: Fair II-2 R Y Y [25] (2008) 15 TMJ, numbers unclear Unclear NR 0.60 Fair II-2 P Y Y [31] (2008) 32 TMJ, numbers unclear 8 9 (median) 7: Good II-2 P Y Y Y Y Y [26] (2010) TMJ 9.27 (mean) 8: Fair II-2 P Y [32] (2009) TMJ 9.8 (mean) 14: Good II-2 P Y Y Y Y [33] (2011) TMJ 11.2 (mean) 11: Good II-3 R Y Y [34] (2010) 59 SI of 21 patients 9.33 (mean) 40: Good II-3 R Y Y Y [27] (2009) TMJ 12.7 (mean) 19: Fair II-2 P Y Y [18] (2010) TMJ 13.5 (median) 5: Fair II-3 R Y Y [19] (2003) joints (punctured) 12.9 (mean) 62: Poor II-2 P Y Y Y Y [37] (2011) TMJ (mean) 4: Poor II-3 R Y [30] (2012) 50 Thoracic and lumbar spine 14.8 (median) 9: Fair II-2 R Y [28] (2012) TMJ 9.5 (mean) 20: Fair II-3 R Y Y [29] (2012) TMJ 6.7 (mean) 71: Fair II-2 R Y Note JIA = juvenile idiopathic arthritis, Qual = qualitative, Semi = semiquantitative, PI = predictive index, EI = evaluative index, DI = discriminative index, Resp = responsiveness, TMJ = temporomandibular joint, Y = yes, CS = cervical spine, SI = sacroiliac joint, P = prospective, R = retrospective, NR = not reported. a Construct validity: This clinimetric property is defined as the extent to which a particular measure relates to other measures in a manner that is consistent with theoretically derived hypotheses concerning the concepts (or constructs) that are being measured [43]. b Predictive index: An index that is used to classify individuals into a set of predefined measurement categories when a reference standard is available, either concurrently or prospectively, to determine whether individuals have been classified correctly [43]. c Evaluative index: An index that is used to measure the magnitude of longitudinal change in an individual or group on the dimension of interest [43]. d Discriminative index: An index that is used to distinguish between individuals or groups on an underlying dimension when no external criterion or reference standard is available for validating these measures [43]. e Criterion validity: This clinimetric property is defined as the extent to which a measure produces the same results as a reference standard or criterion measure [43]. f Reliability: This clinimetric property is defined as the extent to which repeated measurements of a stable phenomenon get similar results by different people and instruments and at different times and places [44]. g Responsiveness: This clinimetric property is defined as the ability of a measure to detect change in outcomes when one is present (power of the measure to detect a difference) [45]. h Due to subsequent examinations of the same 15 patients. AJR:202, January

4 Munir et al. TABLE 2: Grading of Levels of Evidence According to the Guidelines of the U.S. Preventive Services Task Force [46] Grade Definition I Evidence obtained from at least one properly randomized controlled trial II-1 Evidence obtained from well-designed controlled trials without randomization II-2 Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than one center or research group II-3 Evidence obtained from multiple time series with or without intervention; dramatic results in uncontrolled experiments could be regarded as this type of evidence III Opinions of respected authorities based on clinical experience, descriptive studies and case reports, or reports of expert committees 1789 Search results identified in MEDLINE, EMBASE, DARE, and Cochrane Library databases 38 Articles retrieved for full-text article review 21 Articles considered for inclusion 21 Full-text articles included stage, disagreements were discussed and resolved in a consensus meeting. In contrast, because of logistical reasons, two selected articles written in German were reviewed by one individual and were subsequently discussed and evaluated with two other reviewers. Inclusion Criteria Included in the systematic review were studies that tested clinimetric elements, such as inter- or intrareader reliability (or both) of interpretation of MRI findings; construct validity based on a priori designed hypotheses of correlations between MRI findings or scores and clinical or laboratory findings or scores; criterion validity based on comparison of MRI findings or scores with a reference standard; and the ability of MRI findings or scores to show changes in the joints in response to treatment. We also recorded the role of MRI in the selected studies concerning evaluative, discriminative, and predictive elements regardless of whether this information was explicitly stated in the primary studies. Selected studies included topics on diagnosis, analysis, and interpretation of MRI and the ability of MRI to detect the responsiveness of joints to local or systemic treatment. This systematic review included randomized or quasirandomized cohorts 17 Articles excluded for the following reasons: Duplicate articles (n = 9) Age of patients (n = 5) Too few patients (n = 1) Not focused on JIA (n = 2) 0 Articles included from bibliographic references Fig. 2 Flow diagram shows search and selection process used for identification and quality assessment of articles. JIA = juvenile idiopathic arthritis. (prospective or longitudinal, retrospective) and case-control clinical trials in any phase and metaanalyses. Studies had to pertain specifically to MRI of JIA in the axial joints (TMJ, sacroiliac joints, and spine) and, in case of follow-up studies, an MRI examination had to have been conducted at baseline as well. Studies were included if the mean or median age of participants was 18 years or younger at baseline. Case reports, case reviews, case series, pictorial essays, economic evaluations, decisionanalysis models, descriptive studies, review articles, opinion letters, expert narratives, and comments were excluded. Studies that focused on the peripheral joints (i.e., knees, hips, elbows, ankles) and studies that consisted of fewer than 10 children with JIA were excluded. Also excluded were studies written in languages other than English, French, German, Italian, Spanish, or Portuguese. Data Extraction The following data were extracted from all included studies: characteristics of the study, number of participants, demographic information about participants, and clinimetric properties of the selected studies (Table 1). Data were extracted independently by the reviewers, and the results were compared. Disagreements were resolved by consensus by referring to the original article. Assessment Tool for Quality of Reporting The quality of reporting of the included studies was assessed using the Standards for Reporting of Diagnostic Accuracy (STARD) statement [15]. These standards were developed to improve the reporting of studies on diagnostic accuracy; hence, STARD is a valuable tool to critically appraise the selected studies in a semiquantitative fashion [15]. The reviewers independently analyzed the studies to locate and assess the quality of the description of each STARD item (25 items), providing a rating for each item as adequately described (yes = 1), not described (no = 0), partially described (unclear = 0.5), or not applicable. Disagreements in the scoring of items were discussed and resolved by consensus. The scores for the 25 items (or for those applicable) were added together where the maximum total numerical score (25 or total for applicable items) for a given article represented 1.00 (100%) and the minimum total score (0) represented 0.00 (0%), with the remainder total scores proportions of individual articles ranging between 0.00 (0%) and 1.00 (100%). Each article was graded as poor ( ), fair ( ), or good ( ) based on the overall numeric score. Assessment Tool for Methodologic Quality For assessment of methodologic quality, studies were evaluated by two readers conjointly who reached a consensus for grading of the level of evidence according to the guidelines of the Canadian Task Force on Preventive Health Care [17] (Table 2). Results Selection of Studies The electronic literature search retrieved 1789 unique citations. After selection based on the title and keywords and subsequent assessment of the abstracts of these studies, 38 citations were selected. On the basis of the inclusion criteria, 21 studies were selected for further evaluation and retrieval and were chosen for the review (Fig. 2). Included were stud- 202 AJR:202, January 2014

5 MRI for Diagnosis of JIA in the Axial Joints STARD Item Proportion of Studies in Which Item Was Reported, Partially Reported, Not Reported, or Not Applicable (%) Item 1: Study of diagnostic accuracy Item 2: States research questions or aims Item 3: Describes study population, inclusion criteria, and setting Item 4: Describes patient recruitment Item 5: Describes participant sampling Item 6: Describes data collection Item 7*: Describes a reference standard with rationale Item 8: Provides technical specifications of tests Item 9*: Describes cutoffs and units for tests Item 10: Describes the readers Item 11: Describes blinding Item 12: Describes statistical methods Item 13: Describes methods used to calculate reliability Item 14: Provides time frame of the study Item 15: Provides the clinical and demographic characteristics of the patients Item 16: Reports failures to test Item 17: Reports time interval between tests Item 18: Reports distribution of disease severity Item 19: Cross-tabulates the results from all tests Item 20: Reports adverse events Item 21: Reports result uncertainty Item 22: Reports indeterminate results, missing responses, and outliers Item 23: Reports variability between subgroups, readers, or centers Item 24: Reports reliability results Item 25: Discusses clinical applicability of findings Fig. 3 Graphic display of Standards for Reporting of Diagnostic Accuracy (STARD) assessment of quality of reporting. Asterisk = item not applicable when no reference standard is identified. ies in which validity (18/21 [86%] articles), responsiveness (6/21 [29%]), and reliability (4/21 [19%]) were assessed; some of the included articles measured more than one clinical property. Fifteen of the 21 (71%) studies evaluated the TMJs, four (19%) evaluated the sacroiliac joints, and two (10%) evaluated the spinal joints. Nineteen of the 21 (90%) articles were written in English, whereas the remaining two articles were written in German [18, 19]. Reported Partially reported Not reported Not applicable Overall Quality of Reporting Using the STARD statement, reviewers graded 13 of the 21 (62%) articles as fair [7, 18, 20 30], four of 21 (19%) as good [31 34], and four of 21 (19%) as poor [19, 35 37] in terms of the quality of reporting. None of the studies had a reference standard used against MRI as a construct, and therefore several of the STARD items did not apply; the scoring and grading of these articles were determined with this characteristic in consideration. Figure 3 illustrates the distribution of ratings according to the various STARD items. Nine of 21 (43%) studies [7, 19, 21, 22, 24, 25, 29, 32, 34] identified a reference standard, although no study used MRI as a construct to evaluate criterion validity against another reference standard. Therefore, STARD items 7 and 9, which required a reference standard, were not applicable for most studies. Only five of 21 studies (24%) [18, 21, 31, 33, 34] reported the reliability of tests (STARD item 24). Other STARD items that had less than 50% adequate reporting included the following: study population description (item 3); reader description (item 10); blinding (item 11); reporting failure to test (item 16); reporting adverse events (item 20); reporting result uncertainty (item 21); and reporting indeterminate, missing, and outlying results (item 22). Summary of Evidence Reliability of MRI for Depicting Findings Suggestive of Juvenile Idiopathic Arthritis: Items 1 and 2 in Figure 1 Temporomandibular joint Two (10%) studies (level of evidence: II-2 [n = 1] and II-3 [n = 1]) [31, 33] examined the reliability of MRI findings in TMJs. Weiss et al. [31] (level of evidence, II-2 [n = 1]) found perfect interobserver (two radiologists) overall agreement for any acute or chronic disease findings. However, there was lower agreement for individual signs: Agreement for the detection of effusion and synovial thickening on unenhanced MRI was 75% and 62.5%, respectively. Abramowicz et al. [33] (level of evidence, II-3 [n = 1]) reported almost perfect agreement between two radiologists (κ = 0.948). Mussler et al. [18] (level of evidence, II-3 [n = 1]) found an overall good agreement (κ = 0.9) between two radiologists (both blinded for clinical information) who reviewed MRI examinations of 34 JIA patients with TMJ involvement. Sacroiliac joints One study (5%), Pagnini et al. [34] (level of evidence, II-3), found moderate to substantial agreement (κ = ) between two radiologists for sacroiliac joint findings. Spinal joints No study examined the reliability of MRI findings in the spine. Accuracy of MRI for the Diagnosis of Early Joint Changes: Item 1 in Figure 1 Question 1: Can MRI be used to detect early axial joint changes? Of the 21 articles, 18 (86%) investigated the validity of MRI for the evaluation of early joint changes in children with JIA, including 14 (67%) articles on TMJs (level of evidence, II-2 [n = 10] and II-3 [n = 4]) [7, 18, 22 29, 31 33, 35], three (14%) articles on sacroiliac joints (level of evidence, II-2 [n = 2] and AJR:202, January

6 Munir et al. II-3 [n = 1]) [20, 21, 34], and one (5%) article (level of evidence, II-3 [n = 1]) [36] on spinal joints. Eleven (52%) articles used contrast material to evaluate synovial characteristics and soft-tissue inflammation (level of evidence, II-2 [n = 9] and II-3 [n = 2]) [20 24, 26, 27, 29, 32 34]. Contrast-enhanced MRI was superior in the detection of synovial hypertrophy or early joint inflammation compared with radiography in eight (38%) articles (level of evidence, II-2 [n = 5] and II-3 [n = 3]) [7, 20, 21, 23, 25, 34 36] and compared with ultrasound in two (10%) articles (level of evidence, II-2 [n = 2]) [31, 32]. Temporomandibular joint Several studies concluded that MRI was able to detect early JIA outcomes in TMJs, such as pannus (level of evidence, II-2 [n = 4] and II-3 [n = 1]) [7, 23, 25, 31, 35], joint effusions (level of evidence, II-2 [n = 6] and II-3 [n = 3]) [22, 23, 25, 26, 28, 29, 32, 33, 35], and synovial enhancement (level of evidence, II-2 [n = 6] and II-3 [n = 2]) [7, 23, 25, 26, 28, 29, 32, 33]. In one study (5%; level of evidence, II-2) [29], nearly 66% of TMJs with acute findings would have been interpreted as normal without IV contrast material. One study (5%; level of evidence, II-2) [23] did not consider bone marrow enhancement to be an effective indicator of early changes. This issue is a controversial one because other studies in adults, such as that by Kothari et al. [38] (which is out of the scope of this article), have shown that bone marrow lesions detected on MRI tend to increase the risk of knee osteoarthritis progression and be predictive of subregional cartilage loss. MRI was deemed to be superior to radiography (level of evidence, II-2 [n = 3] and II-3 [n = 1]) [7, 23, 25, 35], ultrasound (level of evidence, II-2 [n = 2]) [31, 32], rheumatologic examinations (level of evidence, II-2 [n = 1]) [32], orthodontic examinations (level of evidence, II-2 [n = 1]) [32], and general and musculoskeletal clinical examinations (level of evidence, II-2 [n = 1]) [26] in detecting early changes, all of which had poor agreement with MRI. One study (level of evidence, II-2 [n = 1]) [25]found radiographs obtained by orthopantomogram imaging to have a lower frequency of detection of changes (p < 0.003) compared with MRI. Similarly, another study (level of evidence, II-2 [n = 1]) [7] found synovial enhancement on MRI in 87% of patients as opposed to radiography, which detected TMJ involvement in 40% of patients. Taylor et al. [35] (level of evidence, II-3 [n = 1]) qualitatively reported a comparable but higher rate of detection for MRI compared with radiography. Ultrasound had 23 81% sensitivity and % specificity compared with MRI (level of evidence, II-2 [n = 2]) [31, 32]. Müller et al. [32] (level of evidence, II-2 [n = 1]) found a sensitivity and specificity of 47% and 75%, respectively, for rheumatologic examinations and 66% and 46% for orthodontic examinations. Abdul-Aziez et al. [26] (level of evidence, II-2 [n = 1]) found a significant increase in the mean Childhood Health Assessment Questionnaire (CHAQ) score (t value = 4.0, p < 0.05), erythrocyte sedimentation rate (ESR) (t value = 6.0, p < 0.001), C-reactive protein level (t value = 7.9, p < 0.001), synovial enhancement (t value = 5.8, p < 0.001), and effusion scores (t value = 3.5, p < 0.05) in patients with active disease compared with those who were in remission. Two studies concluded that contrast material was essential to discriminate between synovium hypertrophy and joint effusion (level of evidence, II-2 [n = 1] and II-3 [n = 1]) [7, 35]. One study (5%) suggested that TMJ involvement in JIA is underdiagnosed without imaging (level of evidence, II-2 [n = 1]) [27], and two other studies (10%) suggested that JIA patients without clinical signs should be eligible for MRI examination because of the lack of correlation found between MRI and clinical examination (level of evidence, II-2 [n = 2]) [23, 29]. Mussler et al. [18] (level of evidence, II-3 [n = 1]) reported the ability of MRI to detect contrast enhancement (in 65 76% of cases) based on the interpretation of two radiologists who considered synovial contrast enhancement as a sign of active inflammation in the TMJ. Sacroiliac joints Depending on the type of patient group, two studies (10%; level of evidence, II-2 [n = 1] and II-3 [n = 1]) [21, 34] detected higher proportions of early sacroiliac joint outcomes such as bone marrow edema, joint enhancement, and mild subchondral sclerosis with both unenhanced and contrast-enhanced MRI compared with conventional radiography, which failed to detect any early sacroiliac joint outcome. Another study (level of evidence, II-2 [n = 1]) [20] that investigated only contrast-enhanced MRI against radiography found similar results. Spinal joints Only one study (5%; level of evidence, II-3 [n = 1]) [36] investigated the role of MRI in detecting early changes. This study on the cervical spine concluded that MRI is superior to radiography in visualizing soft-tissue changes, particularly with regard to pannus. In 13 of 20 (65%) asymptomatic patients, pannus proliferation was identified on MRI. This study also suggested that contrast material was not required because of MRI s satisfactory ability to reveal soft-tissue changes and anatomic structures. Accuracy of MRI for the Diagnosis of Intermediate and Late Joint Changes: Item 2 in Figure 1 Question 2: Can MRI be used to detect intermediate and late axial joint changes with regard to the progression of arthropathy? Nineteen (90%) articles investigated the validity of MRI for the evaluation of intermediate joint changes in the axial joints in JIA patients, including 14 articles on TMJs (67%; level of evidence, II-2 [n = 11] and II-3 [n = 3]) [7, 18, 22 29, 31 33, 35], three articles on sacroiliac joints (14%; level of evidence, II-2 [n = 2] and II-3 [n = 1]) [20, 21, 34], and two articles on spinal joints (10%; level of evidence, II-3 [n = 2]) [30, 36]. These studies examined articular cartilage degeneration (level of evidence, II-2 [n = 1] and II-3 [n = 3]) [18, 22, 33, 36], subchondral bone degeneration (level of evidence, II-2 [n = 10] and II-3 [n = 3]) [7, 18, 20, 21, 23 27, 31, 32, 34, 35], and disk degeneration (level of evidence, II-2 [n = 3] and II-3 [n = 3]) [7, 18, 25, 27, 33, 35]. Temporomandibular joint Several studies found that MRI was able to detect articular disk changes in TMJs (level of evidence, II-2 [n = 1] and II-3 [n = 3]) [7, 18, 28, 35], changes in condylar morphology (level of evidence, II-2 [n = 4] and II-3 [n = 3]) [18, 23, 27 29, 32, 35], loss of articular cartilage (level of evidence, II-2 [n = 1]) [22], and erosions (level of evidence, II-2 [n = 5] and II-3 [n = 3]) [7, 18, 23, 25, 26, 28, 29, 35] but noted that contrast material is ineffective at enhancing cartilage (level of evidence, II-2 [n = 1]) [23]. However, these findings were not confirmed by a reference standard. One study (5%; level of evidence, II-3 [n = 1]) [35] qualitatively reported a similarity between the frequency of MRI findings and radiographic findings pertaining to condyle size and shape and the fossa, but the authors noted that MRI had higher rates of detection. Another study (5%; level of evidence, II-2 [n = 1]) [31] comparing ultrasound with MRI found only 50% agreement (κ = 0.12) between the two imaging techniques for the assessment of chronic TMJ changes, and the authors concluded that MRI is superior at detection. Another study (level of evidence, II-3 [n = 1]) [18] reported that MRI is able to detect alterations in the mandibular condyles (88 91% of cases), showing significant correlations between these alterations and TMJ pain (p = 0.03) and decreased mouth opening capacity (p = 0.02), but not between these alterations and disk pathology. Sacroiliac joints Three studies (14%) investigated intermediate outcomes in sac- 204 AJR:202, January 2014

7 MRI for Diagnosis of JIA in the Axial Joints roiliac joints (level of evidence, II-2 [n = 2] and II-3 [n = 1]) [20, 21, 34], all of which compared the results against radiography. One study (level of evidence, II-3 [n = 1]) [34] concluded that contrast-enhanced MRI is more sensitive than conventional radiography because all the radiographs obtained were negative. In contrast, MRI detected changes in joint space width in eight of 17 patients (47%) and erosions in two of 17 patients (12%). Another study (level of evidence, II-2 [n = 1]) [20] reported a significantly higher sensitivity (p < 0.001) for MRI compared with radiography for the detection of both early and intermediate sacroiliac joint changes. Another study (level of evidence, II-2 [n = 1]) [21] also found a higher sensitivity for MRI (p < 0.05) compared with radiography by detecting disease in 29 of 208 joints (14%) by MRI as opposed to 23 of 208 joints (11%) by radiography. Spinal joints One study (5%; level of evidence, II-3 [n = 1]) on cervical spine joints [36] reported poor sensitivity (57%) for radiography compared with MRI: Detection of erosions by MRI was possible in seven patients as opposed to four patients by radiography. Another study (level of evidence, II-2 [n = 1]) [30] examining the thoracic and lumbar spine found that MRI was able to detect vertebral fractures, intervertebral disk degeneration, endplate irregularities, and anterior corner defects, for a total of abnormal findings in 31 (62%) of 50 patients, but these findings did not significantly correlate with bone densitometry measures in the lumbar spine (p > 0.05). Ability of MRI to Detect Responsiveness of Joints to Treatment: Item 3 in Figure 1 Question 3: Is MRI useful to monitor the effect of treatment on improving joint pathology and preventing further damage? Temporomandibular joint Five TMJ articles (24%) reported responsiveness measurements (level of evidence, II-2 [n = 3] and II-3 [n = 2]) [22, 24, 28, 31, 37]. These studies investigated the use of MRI in the detection of changes in synovial hypertrophy as well as changes in articular cartilage, subchondral bone, and articular disk after corticosteroid injections. In the first study (level of evidence, II-2 [n = 1]) [31], six of 24 (25%) patients received corticosteroid injections and were also evaluated for followup changes by MRI. Decreased joint effusions, synovial thickening, or both were found in five of the six (83%) patients, but no improvements were noted in condylar morphology or erosions. In the second study (level of evidence, II-2 [n = 1]) [24], the authors reported a reduction in TMJ effusion in eight of 10 (80%) patients after an average of 9 months of continued treatment. However, in one patient both joints were found to present with worsened effusions, erosions, and bilateral condylar flattening on follow-up MRI. The authors hypothesized that chronic structural changes might not be treated by corticosteroid therapy. Arabshahi et al. [22] (level of evidence, II-2 [n = 1]) found that MRI detected interval resolution of joint effusions in eight of 10 (80%) patients after injection but this finding was not observed for condylar sclerosis. The remaining two (20%) patients presented with persistent joint effusions. In addition, three of 19 (16%) TMJs in 14 patients presented with worsening bony resorption on the follow-up MRI. However, the fourth study (level of evidence, II-3 [n = 1]) [37] reported substantial improvement in most treated joints in terms of pain, tenderness, and stiffness (100%); jaw deviation (92.8%); and chewing dysfunction (71.4%) but failed to report MRI results after treatment. The fifth study (level of evidence, II-3 [n = 1]) [28] found evidence of improvement in 51% (24/47) of joints and complete resolution of TMJ arthritis in 19% (9/47) of joints. Hence, these five studies indicated that resolution of early inflammatory changes was detectable on contrast-enhanced MRI. One study (5%; level of evidence, II-2 [n = 1]) [29] found a low incidence of chronic changes in TMJs (5.4%), and the authors postulated that this finding might be a result of aggressive therapy with biologic drugs and corticosteroids. Although one study (5%; level of evidence, II-3 [n = 1]) [18] did not assess the effect of specific treatments on clinical and MRI outcomes in the TMJ, the authors found discrepancies between the progression of pathologic findings on MRI and decrease in clinical symptoms over time, showing the importance of MRI for follow-up of patients under treatment. Similarly, another study (p < 0.003; level of evidence, II-2 [n = 1]) [25] found that MRI was superior to orthopantomograms in following condylar changes over time. Sacroiliac joints Fischer et al. [19] (level of evidence, II-2 [n = 1]) reported that in a group of nonresponders to nonsteroidal anti inflammatory drugs (NSAIDs) (56/89), 87.5% (49/56) of the patients had a significant decrease in complaints (p < 0.05) after corticosteroid injection into the sacroiliac joints and that this effect lasted for 12 ± 6 months (mean ± SD). Follow-up MRI showed a significant reduction in contrast enhancement of the sacroiliac joints in both groups (NSAID responders and nonresponders). One third of the patients in the group of nonresponders had progression of joint destruction on MRI despite the absence of clinical symptoms; this finding suggests the absence of an association between MRI findings and a clinical response to treatment. Spinal joints No article studied the ability of MRI to detect treatment responsiveness in the spine. Predictive Value of MRI for Functional Status of the Joints: Item 4 in Figure 1 Question 4: If early changes can be evaluated using MRI, can this information be used to predict future cartilage degeneration or the functional status of the joint? None of the selected articles investigated the predictive value of MRI findings, given that the associations between early and intermediate changes and joint function were not measured over time. One study (5%; level of evidence, II-2 [n = 1]) [26] found significant associations between CHAQ scores and synovial enhancement and effusion for TMJs (t value = 3.1, p < 0.05). Several articles evaluated both early joint changes and intermediate changes, such as atlantoaxial subluxation (level of evidence, II-3 [n = 1]) [36], subchondral bone changes (level of evidence, II-2 [n = 3] and II-3 [n = 1]) [7, 21, 23, 35], or disk changes (level of evidence, II-3 [n = 1]) [35] but failed to evaluate associations between them. Only one study (5%; level of evidence, II-2 [n = 1]) [32] found a significant association between early and intermediate changes namely, synovial enhancement and condylar deformities in TMJs (chi-square test, p < ). Associations Between Intermediate and Late MRI Outcomes and Joint Function: Item 5 in Figure 1 Question 5: Can an association be made between intermediate and late findings on MRI and the functional status of the joint? Four articles (level of evidence, II-2 [n = 3] and II-3 [n = 1]) [26, 30, 32, 34] used the CHAQ tool to evaluate joint function at the time of examination. One study (level of evidence, II-2 [n = 1]) [26] found a significant association between CHAQ scores and condylar morphology in TMJs (t value = 3.1, p < 0.05). However, another study [32] did not find a significant association between CHAQ scores and MRI findings in TMJs. The last two studies (level of evidence, II-2 [n = 1] and II-3 [n = 1]) [30, 34] measured both intermediate MRI findings in sacroiliac joints and thoracic and lumbar spines and CHAQ AJR:202, January

8 Munir et al. TABLE 3: Grading of Strength of Recommendations According to Guidelines of the Canadian Task Force on Preventive Health Care [17] Grade A B C D E I Definition There is good evidence to recommend the clinical preventive action There is fair evidence to recommend the clinical preventive action The existing evidence is conflicting and does not allow a recommendation for or against use of the clinical preventive action; however, other factors may influence decision making There is fair evidence to recommend against the clinical preventive action There is good evidence to recommend against the clinical preventive action There is insufficient evidence (in quality or quantity) to make a recommendation; however, other factors may influence decision making scores but did not report the association between them. Six other studies (29%; level of evidence, II-2 [n = 5] and II-3 [n = 1]) [7, 22, 25, 27, 29, 36], without using the CHAQ, correlated intermediate changes in the TMJ specifically, disk and bony condylar head morphology with joint function. One study [25] suggested that a loss of function (as measured by clinical examination and orthopantomograms) occurs during the later stages of JIA as opposed to earlier stages, whereas another study [27] concluded that intermediate outcomes are an independent predictor of abnormal condylar motion. One study (5%; level of evidence, II-2 [n = 1]) [29] found that both mouth-opening deviation findings (odds ratio [OR] = 6.21; 95% CI, ) and maximal incisal opening (r = 0.94; 95% CI, ) had associations with intermediate findings. No other study found significant associations between intermediate TMJ findings and measures of loss of function, including clinical examination and orthopantomograms [7], and history and maximal incisal opening [22]. Similarly, no significant association was found between intermediate findings in cervical spine joints and loss of function by one study (5%; level of evidence, II-3 [n = 1]) [36]. Summary of Recommendations According to the Canadian Task Force on Preventive Health Care Guidelines Table 3 defines the grades used by the Canadian Task Force on Preventive Health Care [17] to characterize the strength of their recommendations, and Tables 4 6 summarize the levels of evidence and recommendation guidelines by joint. Question 1: Can MRI be used to detect early axial joint changes? There is fair evidence in the literature (in quality and quantity) to recommend the use of MRI to detect early JIA changes in TMJs (grade B). However, there is insufficient evidence in the literature (in quantity) to indicate MRI for detecting JIA in spinal (grade I) and sacroiliac (grade I) joints. Question 2: Can MRI be used to detect intermediate and late axial joint changes with regard to the progression of arthropathy? Fair evidence exists in the literature (in quality and quantity) to allow a recommendation for the use of MRI for detecting intermediate JIA changes in TMJs (grade B). However, there is insufficient evidence in the literature (in quantity) to indicate the use of MRI for spinal (grade I) and sacroiliac (grade I) joints. Question 3: Is MRI useful to monitor the effect of treatment on improving joint pathology and preventing further damage? There is insufficient evidence to indicate that MRI is effective at detecting treatment effects in TMJs (grade I). There is no existing literature for sacroiliac (grade I) and spinal (grade I) joints addressing this research question, and hence no recommendation can be made. Question 4: If early changes can be evaluated using MRI, can this information be used to predict future cartilage degeneration or the functional status of the joint? Insufficient evidence is present in the literature to address this research question with regard to TMJ (grade I), sacroiliac joints (grade I), or spinal joints (grade I); therefore, no recommendation can be made. Question 5: Can an association be made between intermediate and late findings on MRI and the functional status of the joint? No studies were found pertaining to this research question for TMJs (grade I), sacroiliac joints (grade I), or spinal joints (grade I). Discussion This systematic review of the literature points toward varying levels of evidence of the diagnostic accuracy of MRI for evaluating early and intermediate joint changes and for assessing clinical responsiveness to treatment in axial JIA joints. Current gaps in the literature of the diagnostic accuracy of MRI for the assessment of JIA axial skeletal joints include a lack of evidence on the following: early joint damage in the spinal and sacroiliac joints; intermediate changes in the spinal and sacroiliac joints; the long-term effect of therapy on all types of axial joints in cases of JIA diagnosed early in the disease course; and the predictive value of MRI in all types of axial joints in early and intermediate stage JIA using specific treatment methods. Although no studies are currently available in the literature to show the long-term effect of therapy on TMJs, short-term ( months) follow-up studies have shown that the majority of children with symptomatic TMJ arthritis improved after intraarticular corticosteroid injection as assessed by MRI [22, 24, 28, 31, 37]. Therefore, this imaging modality holds potential for being a useful tool for long-term follow-up of TMJs according to different therapeutic approaches once the diagnosis of TMJ involvement is made early during the disease course. The limitations of the currently available primary studies in the literature with regard to the benefit of MRI for the treatment of JIA patients and prognosis of TMJ arthritis include a small sample size, the lack of an appropriate control group, incomplete preprocedure and postprocedure imaging, the use of a head coil rather than a surface coil during MR image acquisition, inconsistent measurement and recording of related clinical parameters, and a relatively short follow-up period. These methodologic and technical shortcomings of the currently available studies should be addressed in future studies. Furthermore, there is an overall limitation in terms of the quantity and quality of the studies on the spinal and sacroiliac joints in the current literature, which opens avenues for active investigation on the clinical applications of MRI for the early diagnosis, prognosis, and follow-up of treatment of JIA affecting these joints. 206 AJR:202, January 2014

9 MRI for Diagnosis of JIA in the Axial Joints TABLE 4: Levels of Evidence and Recommendation Guidelines for Temporomandibular Joints (TMJs) According to the Guidelines of the Canadian Task Force on Preventive Health Care [17] Maneuver No. of Articles [Reference No.] Level of Evidence (No. of Studies) Research Design (No. of Studies) Quality of Reporting Per STARD (No. of Studies) GR Diagnostic Accuracy Question 1: Can MRI accurately detect early changes? 14 [7, 18, 22 29, 31 33, 35] II-2 (10), II-3 (4) Unclear cross-sectional (1), prospective cross-sectional with control subjects (2), prospective cross-sectional without control subjects (3), retrospective cross-sectional (2), retrospective cohort (2), prospective cohort with control subjects (2), prospective cohort without control subjects (2) Poor (1), fair (10), good (3) B 14 studies of different types and qualities suggested that MRI, with and without contrast material, can effectively detect early changes in the TMJ, including synovial hypertrophy (pannus), synovial enhancement (synovitis), and joint effusion. However, no II-1 quality articles were present Question 2: Can MRI accurately detect intermediate and late changes? 14 [7, 18, 22 29, 31 33, 35] II-2 (10), II-3 (4) Unclear cross-sectional (1), prospective cross-sectional with control subjects (2), prospective cross-sectional without control subjects (2), retrospective cross-sectional (3), retrospective cohort (2), prospective cohort with control subjects (2), prospective cohort without control subjects (2) Poor (1), fair(10), good (3) B 14 studies of different types and qualities suggested that MRI, with and without contrast material, can effectively detect intermediate changes in the TMJ, including cartilage loss, erosions, and subchondral abnormalities and cysts. However, no II-1 quality articles were present Question 3: Is there an association between MRI evidence of changes and clinical response to treatment? 5 [18, 22, 24, 31, 37] II-2 (3), II-3 (2) Retrospective cohort (3), prospective cohort (2) Poor (1), fair (3), good (1) I Five studies indicated that a relatively large proportion of patients seem to respond to corticosteroid injections in terms of acute signs. However, intermediate changes are less likely to show improvement on MRI with corticosteroid therapy, which was attributed to limitations of the treatment. Two other studies, although did not measure responsiveness, found discrepancies between progression of pathologic findings on MRI and clinical symptoms and orthopantomograms over time, showing the importance of MRI for follow-up of patients under treatment. However, insufficient evidence exists to make a recommendation Question 4: Can MRI accurately predict intermediate and late changes or joint function based on early changes? 0 I No study truly measured the association between early changes and intermediate changes, and early changes and joint function as measured by CHAQ scores by measuring these over time Question 5: Can MRI accurately predict joint function based on intermediate and late changes? 1 [26] II-2 (1) Prospective cross-sectional (1) Fair (1) I Only one study found a significant association between CHAQ scores and intermediate findings Note Dash ( ) indicates not applicable. STARD = Standards for Reporting of Diagnostic Accuracy, GR = grade recommendation, CHAQ = Childhood Health Assessment Questionnaire. AJR:202, January

10 Munir et al. TABLE 5: Levels of Evidence and Recommendation Guidelines for Sacroiliac Joints According to the Guidelines of the Canadian Task Force on Preventive Health Care [17] Maneuver Question 1: Can MRI accurately detect early changes? Question 2: Can MRI accurately detect intermediate changes? Question 3: Is there an association between MRI evidence of changes and clinical response to treatment? Question 4: Can MRI accurately predict intermediate changes or joint function based on early changes? Question 5: Can MRI accurately predict joint function based on intermediate changes? No. of Articles [Reference No.] Concerning the limitations of the methods of this systematic review, one was the fact that we have not used a specific tool for the assessment of the quality of the studies but rather graded levels of evidence according to the Canadian Task Force on Preventive Health Care [17]. In contrast, we used the Quality Assessment of Diagnostic Accuracy Studies (QUA- DAS) [39] tool for a previous study we conducted pertaining to the peripheral joints of patients with JIA [12]. We did not use the QUADAS tool for this review because six of 14 (43%) items in the QUADAS tool and six of the 13 (46%) items of the QUADAS-2 [40] tool require a reference standard, whereas the selected studies for this systematic review failed to provide a reference standard against which MRI was compared as a construct. Hence, the STARD, of which only two of 25 (8%) items require a reference standard for item assessment, was deemed to be Level of Evidence (No. of Studies) Research Design (No. of Studies) 3 [20, 21, 34] II-2 (3) Unclear cross-sectional (1), prospective cross-sectional (1), retrospective cross-sectional (1) 3 [20, 21, 34] II-2 (3) Unclear cross-sectional (1), prospective cross-sectional (1), retrospective cross-sectional (1) 1 [19] II-2 (1) Retrospective cross-sectional (1) a more appropriate tool to measure the quality of reporting of the selected studies, which may have an effect on the overall quality of the study and level of evidence of the study results. In this study, the STARD scores were low overall: Few primary studies adequately reported reliability of MRI interpretation (19%) and other items (< 50%) such as study population and reader description; blinding; failure to test; adverse events; and uncertain, indeterminate, missing, and outlying results. Nevertheless, in other systematic reviews that used the STARD statement for the assessment of the quality of reporting of diagnostic accuracy of ultrasound imaging overall, all items were also poorly reported; for example, in the study by Roposch et al. [41], fewer than 36% of primary studies adequately reported reliability, study population, and other items on process criteria, statistics, and indeterminate results. Of note is the fact that Quality of Reporting Per STARD (No. of Studies) GR Diagnostic Accuracy Fair (2), good (1) I Three studies suggested that MRI is effective at detecting changes in the sacroiliac joint. However, insufficient evidence exists because only three studies pertained to this research question, two of which were published in 1998 Fair (2), good (1) I Three studies concluded that changes in the sacroiliac joint are detectable by MRI. However, insufficient evidence exists because only three studies pertained to this research question, two of which were published in 1998 Poor (1) I One study found that MRI showed a significant reduction in contrast enhancement of sacroiliac joints in both NSAID responders and nonresponders after corticosteroid injection. However insufficient evidence exists to make a recommendation 0 I 0 I Note Dash ( ) indicates not applicable. STARD = Standards for Reporting of Diagnostic Accuracy, GR = grade recommendation, NSAID = nonsteroidal antiinflammatory drug. neither in our study nor in the Roposch et al. study were indeterminate results reported or sources of heterogeneity in reviewers readings discussed. In systematic reviews that evaluated the quality of reporting of diagnostic accuracy of MRI in peripheral JIA joints [42], the overall STARD scores were also low, with only 22% of studies having adequately reported exclusion criteria, motion artifacts, and the need for patient sedation for imaging. In the latter systematic review [42], none of the primary studies on the ability of MRI to detect changes over time in joints on treatment used sound statistical methods for the proposed purpose. Like our systematic review, the Miller et al. review [42] found that indeterminate results were not reported in any validity study. Nevertheless, in both our review and that by Miller et al. [42], estimates of interreader agreement for interpretation of MRI findings reported as kappa 208 AJR:202, January 2014