ARTHRITIS & RHEUMATOLOGY Vol. 67, No. 8, August 2015, pp 2250–2256 DOI 10.1002/art.39159 C 2015, American College of Rheumatology V
Detection of Inflammatory Sacroiliitis in Children With Magnetic Resonance Imaging Is Gadolinium Contrast Enhancement Necessary? Pamela F. Weiss,1 Rui Xiao,2 David M. Biko,1 Ann M. Johnson,1 and Nancy A. Chauvin1 Objective. In adults, gadolinium contrast enhancement does not add incremental value to fluid-sensitive sequences for evaluation of bone marrow edema. This study was undertaken to determine if magnetic resonance imaging (MRI) contrast is necessary to assess lesions consistent with inflammatory sacroiliitis in children. Methods. Patients with clinically suspected or diagnosed juvenile spondyloarthritis (SpA) underwent pelvic MRI consisting of multiplanar fluid-sensitive and postgadolinium T1-weighted fat-saturated sequences including dedicated sacral imaging. Three radiologists independently evaluated the fluid-sensitive sequences, and later, the complete study (including postcontrast images). With postcontrast imaging as the reference standard, we calculated the test properties of fluidsensitive sequences for depiction of acute and chronic findings consistent with sacroiliitis. Results. The 51 patients had a median age of 15 years, and 57% were male. Nineteen patients (22 joints) were diagnosed as having sacroiliitis based on postcontrast imaging, and none had synovitis in the absence of bone marrow edema. All 22 joints demonstrated bone marrow edema on both fluid-sensitive and postgadolinium T1-weighted fat-saturated sequences. Eighteen percent of
joints with sacroiliitis had capsulitis, which was observed on both noncontrast and postcontrast imaging. Fifty-nine percent of joints with sacroiliitis had synovitis on postcontrast imaging. Sensitivity, specificity, positive predictive value, and negative predictive value of fluid-sensitive sequences for the detection of acute inflammatory lesions consistent with sacroiliitis using postgadolinium imaging as the reference standard were excellent. Interrater reliability was substantial for all parameters. Conclusion. Our findings indicate that fluidsensitive sequences are sufficient to detect acute and chronic lesions consistent with inflammatory sacroiliitis in children. Children and adolescents with juvenile spondyloarthritis (SpA) are at risk of developing sacroiliitis, or inflammation of the sacroiliac joints. In children with juvenile SpA, early identification of sacroiliitis using magnetic resonance imaging (MRI) may provide an opportunity to alter the disease course. Active inflammatory lesions of the sacroiliac joints attributable to juvenile SpA include bone marrow edema, sacroiliac joint synovitis, erosions, enthesitis, and capsulitis. Sacroiliitis on MRI is defined in adults by the Assessment of SpondyloArthritis international Society (ASAS) criteria as the presence of subchondral or periarticular bone marrow edema (1). The presence of synovitis, enthesitis, and capsulitis is supportive of the diagnosis of sacroiliitis, but their presence in the absence of bone marrow edema is not sufficient to define sacroiliitis (1). In adults, synovitis, enthesitis, and capsulitis seldom occur in the absence of typical bone marrow edema (2,3). The frequency of these inflammatory lesions in the absence of bone marrow edema in children is unknown. The current gold standard in adults for the detection of acute and chronic lesions consistent with
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Supported by the NIH (award R03-AR-062665 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases). 1 Pamela F. Weiss, MD, MSCE, David M. Biko, MD, Ann M. Johnson, MD, Nancy A. Chauvin, MD: Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; 2Rui Xiao, PhD: Children’s Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia. Address correspondence to Pamela F. Weiss, MD, MSCE, 3535 Market Street, Room 1526, Philadelphia, PA 19104. E-mail: [email protected]. Submitted for publication December 8, 2014; accepted in revised form April 9, 2015. 2250
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inflammatory sacroiliitis is dedicated pelvic MR imaging with fluid sequences, including short T1 inversion recovery (STIR) (1,4,5). While both fluid-sensitive and fatsaturated postcontrast sequences can identify enthesitis, capsulitis, and bone marrow edema, only fat-saturated postcontrast sequences can identify synovitis. In adults, multiple studies have shown that since synovitis rarely occurs in the absence of bone marrow edema, gadolinium enhancement does not add incremental value to fluid-sensitive sequences (2,3,6–8). Despite the published reports of findings in adults, the use of gadolinium to evaluate for acute and chronic lesions consistent with inflammatory sacroiliitis in children is common practice. The use of gadolinium contrast agents in children for the detection of acute and chronic lesions consistent with inflammatory sacroiliitis has implications such as the need for vascular access, longer study times which may necessitate the use of sedation, potential adverse contrast events, and increased cost. MRI of the sacroiliac joint does not require vascular access in children unless intravenous (IV) sedatives or contrast agents are required. IV catheter placement may cause intense anxiety (for both the parent and the child) and pain (9–11). The time needed to acquire additional sequences after contrast administration is ;10 minutes in the scanner. If a child needs sedation for the imaging, then that additional time could result in additional sedative administration. Administration of gadolinium contrast also has some potential adverse effects, namely the risk of severe allergic reaction and nephropathy including nephrogenic systemic fibrosis (12–15). The mechanism of gadolinium toxicity in the kidneys is unclear but thought to include vasoconstriction leading to hypoxic tubular cell injury (16). Those children and adults with renal failure are at the highest risk of nephrogenic systemic fibrosis (16). Last, administration of contrast adds costs; at our institution the use of contrast to image the sacroiliac joints adds ;$1,800. Given that the use of gadolinium in children is not risk free, it should not be used indiscriminately for the evaluation of acute and chronic lesions consistent with inflammatory sacroiliitis unless it adds incremental value to fluid-sensitive sequences. The purpose of this study was to determine if MRI contrast is necessary to assess for sacroiliitis in patients with clinically suspected or diagnosed juvenile SpA. With postcontrast imaging as the reference standard, we aimed to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of fluid-sensitive sequences for the depiction of acute and chronic lesions consistent with inflammatory sacroiliitis in children.
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PATIENTS AND METHODS Study approval. The Committee for the Protection of Human Subjects at the Children’s Hospital of Philadelphia approved the protocol for the conduct of this study. Study patients. Patients included males and females who underwent MR imaging of the pelvis consisting of multiplanar fluid-sensitive and postgadolinium T1-weighted fatsaturated sequences that included small field-of-view oblique coronal imaging of the sacrum between January 2002 and April 2014 at our institution. Clinical data. Demographic characteristics and indications for imaging were abstracted from the electronic medical health record. Imaging. All pelvis and hip MR images in our radiology picture archiving and communication system from January 2002 to April 2014 were queried to identify the terms “sacroiliitis”, “arthritis”, “pain”, “stiffness”, “spondyloarthritis”, “inflammation”, and “spondyloarthropathy” in the requisition or study report using the Softek Illuminate search engine (n 5 97). All images were screened to ensure that both fluidsensitive sequences and fat-saturated T1-weighted postcontrast images were obtained (n 5 95). Only studies with dedicated pelvic images, defined as inclusion of an oblique coronal (parallel to the long axis of the sacrum) view of the sacrum, were included (n 5 54). All records were screened to verify that the imaging was ordered as part of an evaluation for known or suspected juvenile SpA (n 5 51). Magnet strength was 1.5T (n 5 27) or 3.0T (n 5 24). MRI slices through the sacrum were 3 mm thick. All fluid-sensitive sequences and fat-saturated T1weighted postcontrast images were deidentified and read by 3 pediatric radiologists with experience in musculoskeletal imaging (NAC, DMB, and AMJ). Three radiologists, who were blinded with regard to clinical details, independently evaluated the noncontrast sequences, and at a later date, the complete study (including postcontrast imaging) in randomized order. Images were evaluated for the presence of bone marrow edema, capsulitis, effusion, and synovitis (postcontrast sequences only). During an initial consensus review of 5 cases, which were not included in our study, standards of interpretation and terminology were established. To avoid interpretation fatigue, the readings were done in sets of 8 studies, with a maximum of 1 set interpreted at a time. Findings were considered positive if noted by 2 of the 3 radiologists. The ASAS/Outcome Measures in Rheumatology (OMERACT) definitions of active inflammatory lesions including bone marrow edema, synovitis, capsulitis, and enthesitis were used for this study (6). Bone marrow edema was defined as hyperintense signal on T2-weighted fat-saturated imaging or STIR images. If there was one detectable lesion, then the lesion had to be present on more than one consecutive imaging slice. If there was more than one lesion present on a single slice, then 1 slice was considered sufficient evidence of inflammation (1). In children who were skeletally immature, care was taken to avoid identifying bone marrow edema as present in patients with relatively hyperintense apophyseal cartilage adjacent to the sacroiliac joints (7). In these patients, edema was diagnosed when the STIR signal was hyperintense relative to the signal in the visualized metaphyseal equivalents (i.e., iliac crest apophyses), which were used as reference standards. Sacroiliitis was defined as the presence of bone marrow edema in periarticular areas. Synovitis was defined as
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Table 1.
Sacroiliac lesions detected on magnetic resonance imaging (n 5 102 joints)*
Bone marrow edema Enthesitis Capsulitis Synovitis Joint effusion Erosions Sclerosis
Fluid-sensitive sequences and full study
Fluid-sensitive sequences only
22 (22) 0 (0) 4 (4) – 4 (4) 10 (10) 1 (1)
3 (3) 2 (2) 2 (2) – 2 (2) 1 (1) 0 (0)
Full study only 0 0 0 13 0 4 1
(0) (0) (0) (13) (0) (4) (1)
* Values are the number (%) of joints with active inflammatory sacroiliac lesions detected on both fluid-sensitive (noncontrast) sequences and the full study (including the postcontrast sequences), fluidsensitive sequences only, and the full study including postcontrast sequences only. Findings were considered positive if noted by at least 2 of the radiologists.
abnormal synovial enhancement in the inferior aspect of the joint, based on prior studies that demonstrated that true synovial lining is confined to the distal third of the joint (17). Capsulitis was defined as hyperintense fluid-sensitive signal or abnormal enhancement adjacent to the anterior or posterior sacroiliac joint capsule. Enthesitis was defined as increased fluid-sensitive signal or abnormal enhancement within the ligamentous aspects of the joint. The ASAS/OMERACT definitions of structural damage lesions including sclerosis and erosions were used for this study (6). Sclerosis was defined as low or absent signal that extends at
least 5 mm from the sacroiliac joint space. Erosions were defined as bony defects along the sacroiliac joint margin with low and high signals on T1-weighted and STIR sequences, respectively. Statistical analysis. Patient demographic information and characteristics were summarized as frequencies and percentages for categorical values and presented as the mean 6 SD or median and interquartile range (IQR), as appropriate, for continuous variables. The sensitivity, specificity, PPV, and NPV of fluid-sensitive sequences for depiction of sacroiliitis were calculated using postcontrast imaging as the reference standard. The interrater reliability of the
Figure 1. Active inflammatory lesions of the sacroiliac joints visible on both fluid-sensitive and postcontrast sequences in a 17-year-old boy with left lower back pain. A, Oblique coronal short T1 inversion recovery image of the sacrum, demonstrating periarticular bone marrow edema within the left sacrum and left iliac bone (solid arrows). There is a small amount of joint fluid within the left sacroiliac joint with adjacent capsular edema (arrowheads). There is edema at the gluteal muscle origin (broken arrow). B, Oblique coronal T1-weighted postcontrast imaging of the sacrum, demonstrating enhanced periarticular bone marrow (solid arrows), adjacent synovitis (encircled area) as demonstrated by periarticular enhancement within the inferior, synovial lined portion of the joint space, capsulitis (arrowheads), and enhanced inflammation at the gluteal muscle origin (broken arrow).
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Figure 2. Active inflammatory lesions and normal findings in skeletally immature sacroiliac joints visible on both fluid-sensitive and postcontrast sequences in an 8-year-old male patient with right lower back pain. A, Oblique coronal short T1 inversion recovery image of the sacrum, demonstrating bone marrow edema within the inferior periarticular aspect of right iliac bone (solid arrow). There is a small amount of joint fluid within the inferior aspect of the joint (arrowhead). A normal hyperintense subchondral stripe is seen on the left in this skeletally immature child (broken arrow). B, Oblique coronal T1-weighted postcontrast image of the sacrum, demonstrating enhanced bone marrow edema within the inferior right iliac bone (solid arrow) and adjacent synovitis within the inferior, ventral aspect of the joint (arrowheads) with adjacent periarticular enhancement, which is greater on the iliac side. There is a normal, mild enhancement of the left segmental sacral apophyses (broken arrow).
MR interpretation for bone marrow edema, capsulitis, effusion, and synovitis was measured with Fleiss’ kappa coefficients (18). Enthesitis and capsulitis as well as erosions and sclerosis were pooled for the purposes of assessing reliability given the low numbers of abnormal findings. According to Landis and Koch (19), a kappa value of #0.40 indicates poor agreement, 0.41–0.59 indicates fair agreement, 0.60–0.74 indicates good agreement, and $0.75 indicates excellent agreement. Statistical analyses were performed using Stata software, version 13.
RESULTS Demographic characteristics of the patients. Images from 51 patients with clinically suspected or diagnosed juvenile SpA were included. Patients had a median age of 15 years (IQR 13–16 years; range 4–19 years). Eleven children were older than 16 years at the time of imaging, but each had symptom onset prior to age 16. Twentynine (57%) were male. Seventy-five percent, 18%, 6%, and 2% were white, African American, Asian, or other race, respectively. The indication for imaging was back pain in 46 (90%), hip pain in 3 (6%), and decreased back flexion in 2 (4%). After imaging, 43 patients had a confirmed diagnosis of juvenile SpA, and 8 were diagnosed as having other conditions, including infection (n 5 2), fibromyalgia (n 5 1), and back pain not otherwise specified (n 5 5). All children with juvenile SpA met the International League of Associations for Rheumatology criteria (20) for enthesitis-related arthritis (n 5 31) or
psoriatic arthritis (n 5 4) or the European Spondyloarthropathy Study Group Criteria for SpA (21) (n 5 8). MRI findings. MRI results are presented in Table 1. Twenty-two joints in 19 patients had sacroiliitis based on postcontrast imaging, using the ASAS criteria (1). All 22 joints demonstrated bone marrow edema on both fluid-sensitive and postgadolinium T1-weighted fat-saturated sequences (Figures 1 and 2). The majority of capsulitis, effusions, and erosive lesions were visualized on both fluid-sensitive and postgadolinium images. Two cases of enthesitis were seen only on fluid-sensitive images. In those few instances where erosions (n 5 4) or sclerosis (n 5 1) were detectable solely in the full study with postcontrast images, the diagnosis of sacroiliitis did not change, since they all occurred in the presence of bone marrow edema on fluid-sensitive sequences. Table 2. Active inflammatory sacroiliac lesions detected on magnetic resonance imaging in the presence or absence of bone marrow edema (n 5 102 joints)*
Enthesitis Capsulitis Synovitis
Bone marrow edema positive (n 5 22)
Bone marrow edema negative (n 5 77)
0 (0) 4 (18) 13 (59)
0 (0) 0 (0) 0 (0)
* Values are the number (%) of joints with active inflammatory sacroiliac lesions detected in the full study (including the postcontrast sequences) in the presence or absence of bone marrow edema seen on the noncontrast images.
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Table 3. Test properties of sacroiliitis depicted by fluid-sensitive sequences, using the full study with postcontrast sequences as the reference standard Sacroiliitis diagnosed on fluid-sensitive sequences Sensitivity Specificity Positive predictive value Negative predictive value
Estimate (95% CI)* 1.00 0.96 0.88 1.00
(0.85–1.00) (0.89–0.99) (0.69–0.97) (0.95–1.00)
ogists with experience in musculoskeletal imaging. Each radiologist independently evaluated the noncontrast sequences, and at a later date, the complete study (including postcontrast images) in randomized order. Interrater reliability using Fleiss’ kappa was substantial (.0.60) for all parameters except for the presence of capsulitis or enthesitis in the full study including postcontrast images (Table 4).
* 95% CI 5 95% confidence interval.
DISCUSSION Thirteen joints had detectable synovitis on postcontrast imaging. Care was taken to avoid identifying bone marrow edema as present in patients with relatively hyperintense apophyseal cartilage adjacent to the sacroiliac joints (Figure 1). Using the full study that included postcontrast sequencing as the reference standard, 0%, 18%, and 59% of joints with sacroiliitis also had enthesitis, capsulitis, or synovitis depicted, respectively. All cases of capsulitis and synovitis that were detected in the full study (including postcontrast sequences) occurred in the presence of bone marrow edema (Table 2). Sensitivity, specificity, PPV, and NPV of fluidsensitive sequences for the detection of bone marrow edema using the full study with postgadolinium sequences as the reference standard were near perfect (Table 3). Five patients had bone marrow edema in the pelvis or hips that was not periarticular. Only one of these patients did not also have periarticular bone marrow edema. Sites of this nonspecific edema included the lesser trochanter, greater trochanter apophysis, femoral heads, and S2. Reliability of MRI findings. All fluid-sensitive sequences and fat-saturated T1-weighted postcontrast images were deidentified and read by 3 pediatric radiolTable 4. Interrater reliability for active inflammatory lesions of the sacroiliac joints* Findings Fluid-sensitive sequences Bone marrow edema Capsulitis/enthesitis Erosions/sclerosis Full study including postcontrast sequences Bone marrow edema Capsulitis/enthesitis Synovitis Erosions/sclerosis
Fleiss’ kappa (95% CI) 0.81 (0.70–0.92) 0.62 (0.51–0.74) 0.61 (0.50–0.72) 0.71 0.50 0.61 0.75
(0.60–0.82) (0.39–0.61) (0.49–0.72) (0.64–0.86)
* Interrater reliability of 3 pediatric radiologists for the detection of active inflammatory lesions of the sacroiliac joint. According to Landis and Koch (19), a kappa value of 0.60–0.74 indicates good agreement, and a kappa value $0.75 indicates excellent agreement. 95% CI 5 95% confidence interval.
This is the first study to systematically evaluate the utility of contrast for the detection of acute and chronic lesions consistent with inflammatory sacroiliitis in children with suspected or known juvenile SpA. In this cross-sectional retrospective study, we found that the use of gadolinium-enhanced sequences did not add incremental value to fluid-sensitive sequences for the detection of acute and chronic lesions, consistent with inflammatory sacroiliitis in the pediatric population. In a setting of clinical suspicion for SpA, according to the ASAS criteria (1), the presence of subchondral or periarticular bone marrow edema is sufficient to diagnose sacroiliitis in adults. In our study there were 22 joints with active sacroiliitis. Eighteen percent and 59% of joints with sacroiliitis also had capsulitis or synovitis, respectively. The prevalence of these lesions, which are supportive of the diagnosis of sacroiliitis, in our cohort is consistent with what has been published in the literature regarding adults (2). Gadolinium did not enhance the ability to detect bone marrow edema or capsulitis but did enable the detection of synovitis. All cases of synovitis and capsulitis were coincident with bone marrow edema on fluid-sensitive sequences. Last, interrater reliability among 3 pediatric radiologists for bone marrow edema was nearly perfect. Our findings should be interpreted in the context of several limitations. First, our sample size was limited to 51 children (102 sacroiliac joints). However, despite the limited sample size, this is the first study to systematically evaluate the utility of contrast to detect bone marrow edema and other acute and chronic changes that are consistent with sacroiliitis in children. Second, because this was not a prospective study there was no uniformity in the MRI sequences obtained. All sequences did include oblique coronal views to ensure adequate visualization of the sacroiliac joints. While this impacts the uniformity of image attainment, it may actually provide greater generalizability of our findings. A variety of sequence protocols exist across care centers, and both 1.5T and 3.0T magnets are used in everyday practice.
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A few findings from this study warrant additional discussion. First, both fluid-sensitive and gadoliniumenhanced sequences can be used to detect acute and chronic lesions consistent with inflammatory sacroiliitis in children, as evidenced by the substantial Fleiss’ kappa values in our study. However, as mentioned above, the administration of contrast is not without consequences in children, ranging from pain and anxiety (secondary to IV catheter placement) to the risk of severe contrast allergic reaction. Although gadolinium did enhance the detection of synovitis, this finding was uniformly in the presence of bone marrow edema and therefore did not alter the final diagnosis. Second, currently there is no uniformly accepted definition of pediatric sacroiliitis. Since all cases of synovitis, capsulitis, and enthesitis were coincident with bone marrow edema on fluid-sensitive sequences, we believe that the ASAS criteria (1) for sacroiliitis are applicable in children. Since interpretation of synovitis, capsulitis, and enthesitis can vary greatly among radiologists, as evidenced by the Fleiss’ kappa from this study, interpretation of these features as supportive but not diagnostic in children will reduce the likelihood of false positive diagnoses. Additionally, MRI findings need to be clinically correlated, taking into consideration the pretest probability and strength of clinical suspicion. Indeed, our findings are not consistent with a recent case series that suggested synovial enhancement could be seen in the absence of bone marrow edema in children; in that study one-third of cases of sacroiliitis were based on the presence of synovitis in the absence of bone marrow edema (22). A precise definition for synovitis in the study by Lin et al (22) was not provided, and we suspect that the threshold for considering patients to be positive for synovitis was lower than in this study. Histopathologic studies with MRI evaluation have shown that a true synovium is only in the inferior aspect of the joint (17). Thus, when joint capsule enhancement is seen in more proximal aspects, findings of synovitis may be overstated. Accurate diagnosis of sacroiliitis in children has important implications for treatment decisions, namely whether a tumor necrosis factor inhibitor should be used, and future disease monitoring. Last, based on the variety of images reviewed in this study, we suggest that the optimal sequences for evaluation of sacroiliitis in children are the following: oblique coronal STIR, T1 turbo spin-echo, and axial T2 fat saturation through the sacroiliac joints; coronal T2 fat saturation of the entire pelvis; and large field-ofview images to screen for hip pathology. Prior studies correlating MRI to histologic findings in adults have demonstrated that the ventral and dorsal aspects of the
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sacroiliac joints are only visible with oblique imaging (17). These studies recommend inclusion of oblique coronal T1 sections as well as oblique axial STIR/T2 fat saturation for adequate assessment of the entire joint (17). In summary, this is the first study to demonstrate that gadolinium-enhanced sequences are not necessary to evaluate for acute and chronic changes consistent with inflammatory sacroiliitis in children with suspected or definite juvenile SpA. There may be cases in which alternative diagnoses are being entertained, such as infection or tumor, in which the use of gadolinium may still be advisable. Avoidance of unnecessary gadolinium contrast will save time in the scanner, save health care dollars, and obviate the need for precontrast screening blood tests and IV placement unless required for sedation or other purposes.
AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Weiss had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Weiss, Chauvin. Acquisition of data. Weiss, Biko, Johnson, Chauvin. Analysis and interpretation of data. Weiss, Xiao, Chauvin.
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16. Thomsen HS, Morcos SK. Contrast media and the kidney: European Society of Urogenital Radiology (ESUR) guidelines. Br J Radiol 2003;76:513–8. 17. Puhakka KB, Melsen F, Jurik AG, Boel LW, Vesterby A, Egund N. MR imaging of the normal sacroiliac joint with correlation to histology. Skeletal Radiol 2004;33:15–28. 18. Fleiss JL. Measuring nominal scale agreement among many raters. Psychological Bull 1971;76:378–82. 19. Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159–74. 20. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol 2004;31:390–2. 21. Dougados M, van der Linden S, Juhlin R, Huitfeldt B, Amor B, Calin A, et al, and the European Spondylarthropathy Study Group. The European Spondylarthropathy Study Group preliminary criteria for the classification of spondylarthropathy. Arthritis Rheum 1991;34:1218–27. 22. Lin C, MacKenzie JD, Courtier JL, Gu JT, Milojevic D. Magnetic resonance imaging findings in juvenile spondyloarthropathy and effects of treatment observed on subsequent imaging. Pediatr Rheumatol Online J 2014;12:25.
Detection of Inflammatory Sacroiliitis in Children With Magnetic Resonance Imaging Is Gadolinium Contrast Enhancement Necessary? Pamela F. Weiss,1 Rui Xiao,2 David M. Biko,1 Ann M. Johnson,1 and Nancy A. Chauvin1 Objective. In adults, gadolinium contrast enhancement does not add incremental value to fluid-sensitive sequences for evaluation of bone marrow edema. This study was undertaken to determine if magnetic resonance imaging (MRI) contrast is necessary to assess lesions consistent with inflammatory sacroiliitis in children. Methods. Patients with clinically suspected or diagnosed juvenile spondyloarthritis (SpA) underwent pelvic MRI consisting of multiplanar fluid-sensitive and postgadolinium T1-weighted fat-saturated sequences including dedicated sacral imaging. Three radiologists independently evaluated the fluid-sensitive sequences, and later, the complete study (including postcontrast images). With postcontrast imaging as the reference standard, we calculated the test properties of fluidsensitive sequences for depiction of acute and chronic findings consistent with sacroiliitis. Results. The 51 patients had a median age of 15 years, and 57% were male. Nineteen patients (22 joints) were diagnosed as having sacroiliitis based on postcontrast imaging, and none had synovitis in the absence of bone marrow edema. All 22 joints demonstrated bone marrow edema on both fluid-sensitive and postgadolinium T1-weighted fat-saturated sequences. Eighteen percent of
joints with sacroiliitis had capsulitis, which was observed on both noncontrast and postcontrast imaging. Fifty-nine percent of joints with sacroiliitis had synovitis on postcontrast imaging. Sensitivity, specificity, positive predictive value, and negative predictive value of fluid-sensitive sequences for the detection of acute inflammatory lesions consistent with sacroiliitis using postgadolinium imaging as the reference standard were excellent. Interrater reliability was substantial for all parameters. Conclusion. Our findings indicate that fluidsensitive sequences are sufficient to detect acute and chronic lesions consistent with inflammatory sacroiliitis in children. Children and adolescents with juvenile spondyloarthritis (SpA) are at risk of developing sacroiliitis, or inflammation of the sacroiliac joints. In children with juvenile SpA, early identification of sacroiliitis using magnetic resonance imaging (MRI) may provide an opportunity to alter the disease course. Active inflammatory lesions of the sacroiliac joints attributable to juvenile SpA include bone marrow edema, sacroiliac joint synovitis, erosions, enthesitis, and capsulitis. Sacroiliitis on MRI is defined in adults by the Assessment of SpondyloArthritis international Society (ASAS) criteria as the presence of subchondral or periarticular bone marrow edema (1). The presence of synovitis, enthesitis, and capsulitis is supportive of the diagnosis of sacroiliitis, but their presence in the absence of bone marrow edema is not sufficient to define sacroiliitis (1). In adults, synovitis, enthesitis, and capsulitis seldom occur in the absence of typical bone marrow edema (2,3). The frequency of these inflammatory lesions in the absence of bone marrow edema in children is unknown. The current gold standard in adults for the detection of acute and chronic lesions consistent with
The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Supported by the NIH (award R03-AR-062665 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases). 1 Pamela F. Weiss, MD, MSCE, David M. Biko, MD, Ann M. Johnson, MD, Nancy A. Chauvin, MD: Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; 2Rui Xiao, PhD: Children’s Hospital of Philadelphia and Perelman School of Medicine, University of Pennsylvania, Philadelphia. Address correspondence to Pamela F. Weiss, MD, MSCE, 3535 Market Street, Room 1526, Philadelphia, PA 19104. E-mail: [email protected]. Submitted for publication December 8, 2014; accepted in revised form April 9, 2015. 2250
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inflammatory sacroiliitis is dedicated pelvic MR imaging with fluid sequences, including short T1 inversion recovery (STIR) (1,4,5). While both fluid-sensitive and fatsaturated postcontrast sequences can identify enthesitis, capsulitis, and bone marrow edema, only fat-saturated postcontrast sequences can identify synovitis. In adults, multiple studies have shown that since synovitis rarely occurs in the absence of bone marrow edema, gadolinium enhancement does not add incremental value to fluid-sensitive sequences (2,3,6–8). Despite the published reports of findings in adults, the use of gadolinium to evaluate for acute and chronic lesions consistent with inflammatory sacroiliitis in children is common practice. The use of gadolinium contrast agents in children for the detection of acute and chronic lesions consistent with inflammatory sacroiliitis has implications such as the need for vascular access, longer study times which may necessitate the use of sedation, potential adverse contrast events, and increased cost. MRI of the sacroiliac joint does not require vascular access in children unless intravenous (IV) sedatives or contrast agents are required. IV catheter placement may cause intense anxiety (for both the parent and the child) and pain (9–11). The time needed to acquire additional sequences after contrast administration is ;10 minutes in the scanner. If a child needs sedation for the imaging, then that additional time could result in additional sedative administration. Administration of gadolinium contrast also has some potential adverse effects, namely the risk of severe allergic reaction and nephropathy including nephrogenic systemic fibrosis (12–15). The mechanism of gadolinium toxicity in the kidneys is unclear but thought to include vasoconstriction leading to hypoxic tubular cell injury (16). Those children and adults with renal failure are at the highest risk of nephrogenic systemic fibrosis (16). Last, administration of contrast adds costs; at our institution the use of contrast to image the sacroiliac joints adds ;$1,800. Given that the use of gadolinium in children is not risk free, it should not be used indiscriminately for the evaluation of acute and chronic lesions consistent with inflammatory sacroiliitis unless it adds incremental value to fluid-sensitive sequences. The purpose of this study was to determine if MRI contrast is necessary to assess for sacroiliitis in patients with clinically suspected or diagnosed juvenile SpA. With postcontrast imaging as the reference standard, we aimed to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of fluid-sensitive sequences for the depiction of acute and chronic lesions consistent with inflammatory sacroiliitis in children.
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PATIENTS AND METHODS Study approval. The Committee for the Protection of Human Subjects at the Children’s Hospital of Philadelphia approved the protocol for the conduct of this study. Study patients. Patients included males and females who underwent MR imaging of the pelvis consisting of multiplanar fluid-sensitive and postgadolinium T1-weighted fatsaturated sequences that included small field-of-view oblique coronal imaging of the sacrum between January 2002 and April 2014 at our institution. Clinical data. Demographic characteristics and indications for imaging were abstracted from the electronic medical health record. Imaging. All pelvis and hip MR images in our radiology picture archiving and communication system from January 2002 to April 2014 were queried to identify the terms “sacroiliitis”, “arthritis”, “pain”, “stiffness”, “spondyloarthritis”, “inflammation”, and “spondyloarthropathy” in the requisition or study report using the Softek Illuminate search engine (n 5 97). All images were screened to ensure that both fluidsensitive sequences and fat-saturated T1-weighted postcontrast images were obtained (n 5 95). Only studies with dedicated pelvic images, defined as inclusion of an oblique coronal (parallel to the long axis of the sacrum) view of the sacrum, were included (n 5 54). All records were screened to verify that the imaging was ordered as part of an evaluation for known or suspected juvenile SpA (n 5 51). Magnet strength was 1.5T (n 5 27) or 3.0T (n 5 24). MRI slices through the sacrum were 3 mm thick. All fluid-sensitive sequences and fat-saturated T1weighted postcontrast images were deidentified and read by 3 pediatric radiologists with experience in musculoskeletal imaging (NAC, DMB, and AMJ). Three radiologists, who were blinded with regard to clinical details, independently evaluated the noncontrast sequences, and at a later date, the complete study (including postcontrast imaging) in randomized order. Images were evaluated for the presence of bone marrow edema, capsulitis, effusion, and synovitis (postcontrast sequences only). During an initial consensus review of 5 cases, which were not included in our study, standards of interpretation and terminology were established. To avoid interpretation fatigue, the readings were done in sets of 8 studies, with a maximum of 1 set interpreted at a time. Findings were considered positive if noted by 2 of the 3 radiologists. The ASAS/Outcome Measures in Rheumatology (OMERACT) definitions of active inflammatory lesions including bone marrow edema, synovitis, capsulitis, and enthesitis were used for this study (6). Bone marrow edema was defined as hyperintense signal on T2-weighted fat-saturated imaging or STIR images. If there was one detectable lesion, then the lesion had to be present on more than one consecutive imaging slice. If there was more than one lesion present on a single slice, then 1 slice was considered sufficient evidence of inflammation (1). In children who were skeletally immature, care was taken to avoid identifying bone marrow edema as present in patients with relatively hyperintense apophyseal cartilage adjacent to the sacroiliac joints (7). In these patients, edema was diagnosed when the STIR signal was hyperintense relative to the signal in the visualized metaphyseal equivalents (i.e., iliac crest apophyses), which were used as reference standards. Sacroiliitis was defined as the presence of bone marrow edema in periarticular areas. Synovitis was defined as
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Table 1.
Sacroiliac lesions detected on magnetic resonance imaging (n 5 102 joints)*
Bone marrow edema Enthesitis Capsulitis Synovitis Joint effusion Erosions Sclerosis
Fluid-sensitive sequences and full study
Fluid-sensitive sequences only
22 (22) 0 (0) 4 (4) – 4 (4) 10 (10) 1 (1)
3 (3) 2 (2) 2 (2) – 2 (2) 1 (1) 0 (0)
Full study only 0 0 0 13 0 4 1
(0) (0) (0) (13) (0) (4) (1)
* Values are the number (%) of joints with active inflammatory sacroiliac lesions detected on both fluid-sensitive (noncontrast) sequences and the full study (including the postcontrast sequences), fluidsensitive sequences only, and the full study including postcontrast sequences only. Findings were considered positive if noted by at least 2 of the radiologists.
abnormal synovial enhancement in the inferior aspect of the joint, based on prior studies that demonstrated that true synovial lining is confined to the distal third of the joint (17). Capsulitis was defined as hyperintense fluid-sensitive signal or abnormal enhancement adjacent to the anterior or posterior sacroiliac joint capsule. Enthesitis was defined as increased fluid-sensitive signal or abnormal enhancement within the ligamentous aspects of the joint. The ASAS/OMERACT definitions of structural damage lesions including sclerosis and erosions were used for this study (6). Sclerosis was defined as low or absent signal that extends at
least 5 mm from the sacroiliac joint space. Erosions were defined as bony defects along the sacroiliac joint margin with low and high signals on T1-weighted and STIR sequences, respectively. Statistical analysis. Patient demographic information and characteristics were summarized as frequencies and percentages for categorical values and presented as the mean 6 SD or median and interquartile range (IQR), as appropriate, for continuous variables. The sensitivity, specificity, PPV, and NPV of fluid-sensitive sequences for depiction of sacroiliitis were calculated using postcontrast imaging as the reference standard. The interrater reliability of the
Figure 1. Active inflammatory lesions of the sacroiliac joints visible on both fluid-sensitive and postcontrast sequences in a 17-year-old boy with left lower back pain. A, Oblique coronal short T1 inversion recovery image of the sacrum, demonstrating periarticular bone marrow edema within the left sacrum and left iliac bone (solid arrows). There is a small amount of joint fluid within the left sacroiliac joint with adjacent capsular edema (arrowheads). There is edema at the gluteal muscle origin (broken arrow). B, Oblique coronal T1-weighted postcontrast imaging of the sacrum, demonstrating enhanced periarticular bone marrow (solid arrows), adjacent synovitis (encircled area) as demonstrated by periarticular enhancement within the inferior, synovial lined portion of the joint space, capsulitis (arrowheads), and enhanced inflammation at the gluteal muscle origin (broken arrow).
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Figure 2. Active inflammatory lesions and normal findings in skeletally immature sacroiliac joints visible on both fluid-sensitive and postcontrast sequences in an 8-year-old male patient with right lower back pain. A, Oblique coronal short T1 inversion recovery image of the sacrum, demonstrating bone marrow edema within the inferior periarticular aspect of right iliac bone (solid arrow). There is a small amount of joint fluid within the inferior aspect of the joint (arrowhead). A normal hyperintense subchondral stripe is seen on the left in this skeletally immature child (broken arrow). B, Oblique coronal T1-weighted postcontrast image of the sacrum, demonstrating enhanced bone marrow edema within the inferior right iliac bone (solid arrow) and adjacent synovitis within the inferior, ventral aspect of the joint (arrowheads) with adjacent periarticular enhancement, which is greater on the iliac side. There is a normal, mild enhancement of the left segmental sacral apophyses (broken arrow).
MR interpretation for bone marrow edema, capsulitis, effusion, and synovitis was measured with Fleiss’ kappa coefficients (18). Enthesitis and capsulitis as well as erosions and sclerosis were pooled for the purposes of assessing reliability given the low numbers of abnormal findings. According to Landis and Koch (19), a kappa value of #0.40 indicates poor agreement, 0.41–0.59 indicates fair agreement, 0.60–0.74 indicates good agreement, and $0.75 indicates excellent agreement. Statistical analyses were performed using Stata software, version 13.
RESULTS Demographic characteristics of the patients. Images from 51 patients with clinically suspected or diagnosed juvenile SpA were included. Patients had a median age of 15 years (IQR 13–16 years; range 4–19 years). Eleven children were older than 16 years at the time of imaging, but each had symptom onset prior to age 16. Twentynine (57%) were male. Seventy-five percent, 18%, 6%, and 2% were white, African American, Asian, or other race, respectively. The indication for imaging was back pain in 46 (90%), hip pain in 3 (6%), and decreased back flexion in 2 (4%). After imaging, 43 patients had a confirmed diagnosis of juvenile SpA, and 8 were diagnosed as having other conditions, including infection (n 5 2), fibromyalgia (n 5 1), and back pain not otherwise specified (n 5 5). All children with juvenile SpA met the International League of Associations for Rheumatology criteria (20) for enthesitis-related arthritis (n 5 31) or
psoriatic arthritis (n 5 4) or the European Spondyloarthropathy Study Group Criteria for SpA (21) (n 5 8). MRI findings. MRI results are presented in Table 1. Twenty-two joints in 19 patients had sacroiliitis based on postcontrast imaging, using the ASAS criteria (1). All 22 joints demonstrated bone marrow edema on both fluid-sensitive and postgadolinium T1-weighted fat-saturated sequences (Figures 1 and 2). The majority of capsulitis, effusions, and erosive lesions were visualized on both fluid-sensitive and postgadolinium images. Two cases of enthesitis were seen only on fluid-sensitive images. In those few instances where erosions (n 5 4) or sclerosis (n 5 1) were detectable solely in the full study with postcontrast images, the diagnosis of sacroiliitis did not change, since they all occurred in the presence of bone marrow edema on fluid-sensitive sequences. Table 2. Active inflammatory sacroiliac lesions detected on magnetic resonance imaging in the presence or absence of bone marrow edema (n 5 102 joints)*
Enthesitis Capsulitis Synovitis
Bone marrow edema positive (n 5 22)
Bone marrow edema negative (n 5 77)
0 (0) 4 (18) 13 (59)
0 (0) 0 (0) 0 (0)
* Values are the number (%) of joints with active inflammatory sacroiliac lesions detected in the full study (including the postcontrast sequences) in the presence or absence of bone marrow edema seen on the noncontrast images.
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Table 3. Test properties of sacroiliitis depicted by fluid-sensitive sequences, using the full study with postcontrast sequences as the reference standard Sacroiliitis diagnosed on fluid-sensitive sequences Sensitivity Specificity Positive predictive value Negative predictive value
Estimate (95% CI)* 1.00 0.96 0.88 1.00
(0.85–1.00) (0.89–0.99) (0.69–0.97) (0.95–1.00)
ogists with experience in musculoskeletal imaging. Each radiologist independently evaluated the noncontrast sequences, and at a later date, the complete study (including postcontrast images) in randomized order. Interrater reliability using Fleiss’ kappa was substantial (.0.60) for all parameters except for the presence of capsulitis or enthesitis in the full study including postcontrast images (Table 4).
* 95% CI 5 95% confidence interval.
DISCUSSION Thirteen joints had detectable synovitis on postcontrast imaging. Care was taken to avoid identifying bone marrow edema as present in patients with relatively hyperintense apophyseal cartilage adjacent to the sacroiliac joints (Figure 1). Using the full study that included postcontrast sequencing as the reference standard, 0%, 18%, and 59% of joints with sacroiliitis also had enthesitis, capsulitis, or synovitis depicted, respectively. All cases of capsulitis and synovitis that were detected in the full study (including postcontrast sequences) occurred in the presence of bone marrow edema (Table 2). Sensitivity, specificity, PPV, and NPV of fluidsensitive sequences for the detection of bone marrow edema using the full study with postgadolinium sequences as the reference standard were near perfect (Table 3). Five patients had bone marrow edema in the pelvis or hips that was not periarticular. Only one of these patients did not also have periarticular bone marrow edema. Sites of this nonspecific edema included the lesser trochanter, greater trochanter apophysis, femoral heads, and S2. Reliability of MRI findings. All fluid-sensitive sequences and fat-saturated T1-weighted postcontrast images were deidentified and read by 3 pediatric radiolTable 4. Interrater reliability for active inflammatory lesions of the sacroiliac joints* Findings Fluid-sensitive sequences Bone marrow edema Capsulitis/enthesitis Erosions/sclerosis Full study including postcontrast sequences Bone marrow edema Capsulitis/enthesitis Synovitis Erosions/sclerosis
Fleiss’ kappa (95% CI) 0.81 (0.70–0.92) 0.62 (0.51–0.74) 0.61 (0.50–0.72) 0.71 0.50 0.61 0.75
(0.60–0.82) (0.39–0.61) (0.49–0.72) (0.64–0.86)
* Interrater reliability of 3 pediatric radiologists for the detection of active inflammatory lesions of the sacroiliac joint. According to Landis and Koch (19), a kappa value of 0.60–0.74 indicates good agreement, and a kappa value $0.75 indicates excellent agreement. 95% CI 5 95% confidence interval.
This is the first study to systematically evaluate the utility of contrast for the detection of acute and chronic lesions consistent with inflammatory sacroiliitis in children with suspected or known juvenile SpA. In this cross-sectional retrospective study, we found that the use of gadolinium-enhanced sequences did not add incremental value to fluid-sensitive sequences for the detection of acute and chronic lesions, consistent with inflammatory sacroiliitis in the pediatric population. In a setting of clinical suspicion for SpA, according to the ASAS criteria (1), the presence of subchondral or periarticular bone marrow edema is sufficient to diagnose sacroiliitis in adults. In our study there were 22 joints with active sacroiliitis. Eighteen percent and 59% of joints with sacroiliitis also had capsulitis or synovitis, respectively. The prevalence of these lesions, which are supportive of the diagnosis of sacroiliitis, in our cohort is consistent with what has been published in the literature regarding adults (2). Gadolinium did not enhance the ability to detect bone marrow edema or capsulitis but did enable the detection of synovitis. All cases of synovitis and capsulitis were coincident with bone marrow edema on fluid-sensitive sequences. Last, interrater reliability among 3 pediatric radiologists for bone marrow edema was nearly perfect. Our findings should be interpreted in the context of several limitations. First, our sample size was limited to 51 children (102 sacroiliac joints). However, despite the limited sample size, this is the first study to systematically evaluate the utility of contrast to detect bone marrow edema and other acute and chronic changes that are consistent with sacroiliitis in children. Second, because this was not a prospective study there was no uniformity in the MRI sequences obtained. All sequences did include oblique coronal views to ensure adequate visualization of the sacroiliac joints. While this impacts the uniformity of image attainment, it may actually provide greater generalizability of our findings. A variety of sequence protocols exist across care centers, and both 1.5T and 3.0T magnets are used in everyday practice.
USE OF CONTRAST FOR EVALUATION OF SACROILIITIS IN CHILDREN
A few findings from this study warrant additional discussion. First, both fluid-sensitive and gadoliniumenhanced sequences can be used to detect acute and chronic lesions consistent with inflammatory sacroiliitis in children, as evidenced by the substantial Fleiss’ kappa values in our study. However, as mentioned above, the administration of contrast is not without consequences in children, ranging from pain and anxiety (secondary to IV catheter placement) to the risk of severe contrast allergic reaction. Although gadolinium did enhance the detection of synovitis, this finding was uniformly in the presence of bone marrow edema and therefore did not alter the final diagnosis. Second, currently there is no uniformly accepted definition of pediatric sacroiliitis. Since all cases of synovitis, capsulitis, and enthesitis were coincident with bone marrow edema on fluid-sensitive sequences, we believe that the ASAS criteria (1) for sacroiliitis are applicable in children. Since interpretation of synovitis, capsulitis, and enthesitis can vary greatly among radiologists, as evidenced by the Fleiss’ kappa from this study, interpretation of these features as supportive but not diagnostic in children will reduce the likelihood of false positive diagnoses. Additionally, MRI findings need to be clinically correlated, taking into consideration the pretest probability and strength of clinical suspicion. Indeed, our findings are not consistent with a recent case series that suggested synovial enhancement could be seen in the absence of bone marrow edema in children; in that study one-third of cases of sacroiliitis were based on the presence of synovitis in the absence of bone marrow edema (22). A precise definition for synovitis in the study by Lin et al (22) was not provided, and we suspect that the threshold for considering patients to be positive for synovitis was lower than in this study. Histopathologic studies with MRI evaluation have shown that a true synovium is only in the inferior aspect of the joint (17). Thus, when joint capsule enhancement is seen in more proximal aspects, findings of synovitis may be overstated. Accurate diagnosis of sacroiliitis in children has important implications for treatment decisions, namely whether a tumor necrosis factor inhibitor should be used, and future disease monitoring. Last, based on the variety of images reviewed in this study, we suggest that the optimal sequences for evaluation of sacroiliitis in children are the following: oblique coronal STIR, T1 turbo spin-echo, and axial T2 fat saturation through the sacroiliac joints; coronal T2 fat saturation of the entire pelvis; and large field-ofview images to screen for hip pathology. Prior studies correlating MRI to histologic findings in adults have demonstrated that the ventral and dorsal aspects of the
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sacroiliac joints are only visible with oblique imaging (17). These studies recommend inclusion of oblique coronal T1 sections as well as oblique axial STIR/T2 fat saturation for adequate assessment of the entire joint (17). In summary, this is the first study to demonstrate that gadolinium-enhanced sequences are not necessary to evaluate for acute and chronic changes consistent with inflammatory sacroiliitis in children with suspected or definite juvenile SpA. There may be cases in which alternative diagnoses are being entertained, such as infection or tumor, in which the use of gadolinium may still be advisable. Avoidance of unnecessary gadolinium contrast will save time in the scanner, save health care dollars, and obviate the need for precontrast screening blood tests and IV placement unless required for sedation or other purposes.
AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Weiss had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Weiss, Chauvin. Acquisition of data. Weiss, Biko, Johnson, Chauvin. Analysis and interpretation of data. Weiss, Xiao, Chauvin.
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