Arthritis & Rheumatism (Arthritis Care & Research) Vol. 61, No. 7, July 15, 2009, pp 900 –908 DOI 10.1002/art.24507 © 2009, American College of Rheumatology
ORIGINAL ARTICLE
Sensitivity and Specificity of Spinal Inflammatory Lesions Assessed by Whole-Body Magnetic Resonance Imaging in Patients With Ankylosing Spondylitis or Recent-Onset Inflammatory Back Pain ULRICH WEBER,1 JUERG HODLER,1 RAHEL A. KUBIK,2 KASPAR RUFIBACH,3 ROBERT G. W. LAMBERT,4 RUDOLF O. KISSLING,1 CHRISTIAN W. A. PFIRRMANN,1 WALTER P. MAKSYMOWYCH4
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Objective. To determine the diagnostic utility of different spinal inflammatory lesions assessed by whole-body magnetic resonance imaging (MRI) in patients with ankylosing spondylitis (AS) or with recent-onset inflammatory back pain (IBP) compared with healthy controls. Methods. We scanned 35 consecutive patients with AS fulfilling the modified New York criteria, 25 patients with IBP of 2 CIL were recorded (for patients with AS, values for sensitivity, specificity, and positive LR were 69%, 94%, and 12, respectively, and for patients with IBP were 32%, 96%, and 8, respectively). LIL had high specificity (97%) but low sensitivity (31%). Nine controls had >1 CIL, but only 2 controls had >2 CIL. Conclusion. Diagnostic utility of STIR MRI for AS is optimal when >2 CIL are present. A single CIL can be found in up to 26% of healthy individuals.
INTRODUCTION Inflammation of the spine in patients with ankylosing spondylitis (AS) causes substantial morbidity and may eventually lead to disability by progressive ossification of the axial skeleton. In AS, the thoracic spine is the second
Supported by the Walter L. and Johanna Wolf Foundation and the Foundation for Scientific Research at the University of Zurich, Switzerland. Dr. Maksymowych’s work was supported by the Alberta Heritage Foundation for Medical Research. 1 Ulrich Weber, MD, Juerg Hodler, MD, MBA, Rudolf O. Kissling, MD, Christian W. A. Pfirrmann, MD: Balgrist University Hospital, Zurich, Switzerland; 2Rahel A. Kubik, MD, MPH: Cantonal Hospital Baden, Baden, Switzerland; 3Kaspar Rufibach, PhD: Institute for Social and Preventive Medicine, University of Zurich, Zurich, Switzerland; 4Robert
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most frequent region affected by inflammation after the sacroiliac (SI) joints (1,2). Plain radiography is an inadequate imaging modality in early spondylarthritis (SpA), prior to the appearance of structural damage, because it does not directly detect inflammatory lesions of the spine, and also due to technical limitations such as the superposition of lung tissue on the thoracic spine. A growing number of imaging studies in AS over nearly
G. W. Lambert, MD, FRCP, Walter P. Maksymowych, MD, FRCP: University of Alberta, Edmonton, Alberta, Canada. Address correspondence to Ulrich Weber, MD, Department of Rheumatology, Balgrist University Hospital, Forchstrasse 340, 8008 Zurich, Switzerland. E-mail: ulrich.
[email protected]. Submitted for publication October 12, 2008; accepted in revised form March 27, 2009.
Spinal Inflammatory Lesions Assessed by Whole-Body MRI 2 decades have consistently shown that magnetic resonance imaging (MRI) is the most sensitive imaging modality for the detection of inflammatory lesions in the spine (3–5). The recently introduced technique of whole-body MRI, which is based on multichannel technology that uses several coils concurrently, permits scanning of the entire spine within ⬍30 minutes (6). This imaging tool may both contribute to early diagnosis of AS and represent a candidate objective measure of the degree of inflammation in the entire spine and SI joints. The widespread use of MRI for diagnostic or classification purposes requires standardized definitions for the morphologic appearances of inflammatory lesions typically observed in the spine of a patient with AS. The Canada/Denmark International MRI Working Group has recently developed standardized definitions of spinal inflammatory lesions (7,8). Inflammatory lesions are first defined based on their presence in either central (including the spinal canal) or lateral (not including the spinal canal) sagittal slices and then, second, on their anatomic location in relation to the vertebral end plate (vertebral corner versus noncorner). Inflammatory lesions are also recorded in the posterior elements of the spine according to anatomic location (facet joint, spinous process). The goal of this study was to determine the sensitivity, specificity, and diagnostic utility of different inflammatory lesions in the entire spine when assessed by whole-body MRI in patients with AS or with recent-onset inflammatory back pain (IBP) compared with a control group of healthy individuals.
SUBJECTS AND METHODS Subjects. AS and IBP group. We studied 35 consecutive patients with AS who fulfilled the modified New York criteria (9) and 25 patients with IBP of ⱖ3 months and ⱕ24 months’ duration, all of whom were recruited from a single rheumatology outpatient clinic. The plain pelvic radiographs of all 60 patients were independently graded by 2 readers (ROK, UW) for sacroiliitis according to the radiographic modified New York criteria (9). Patients with IBP had to fulfill ⱖ2 of 4 IBP criteria based on patient history (morning stiffness ⬎30 minutes’ duration, improvement in back pain with exercise but not with rest, awakening because of back pain during the second half of the night, alternating buttock pain) (10), and additionally had to show ⱖ1 of the following clinical and laboratory features: good response to nonsteroidal antiinflammatory drugs, peripheral arthritis, enthesitis, dactylitis, uveitis, HLA–B27 positivity, elevated erythrocyte sedimentation rate or C-reactive protein level, and positive family history for SpA. The principal criterion used in this cross-sectional study to allocate patients to the IBP group was a self-reported IBP duration of ⱕ24 months, irrespective of the radiographic SI joint grading. The upper age limit for both patient groups was 45 years, and all patients had active disease as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) global score ⱖ4 and/or a BASDAI item 2 score (assessing spinal pain) of ⱖ4 on a numeric rating scale ranging from 0 –10 (11). All patients were enrolled in
901 a national prospective observational AS cohort, the Swiss Clinical Quality Management in Ankylosing Spondylitis. Control group. Thirty-five healthy age- and sex-matched volunteers from the staff (mainly nurses, physiotherapists, and physicians) of the same university hospital that recruited patients served as controls for the AS group. The youngest 25 controls were selected as the control group for the patients with IBP. The status of a healthy control was defined by the Nordic questionnaire (12). Transient back pain any time during the participant’s lifetime and back pain of 1–7 days’ duration in the 12 months prior to study enrollment was permitted under the following conditions concerning consequences of back pain: no previous inpatient or outpatient treatment by a physician, physiotherapist, chiropractor, or similar medical professional, no sick leave, and no adaptation or change of vocational or everyday activities in the past as a consequence of back pain. The study protocol was approved by the Zurich Cantonal Ethics Committee, Subcommittee for Orthopedics and Rheumatology. The patients and the healthy participants all gave written informed consent. Exclusion criteria. In the AS and IBP group, exclusion criteria were ongoing or previous (within the last 6 months) treatment with tumor necrosis factor ␣ inhibitors or other biologic agents, malignancies or infections affecting the skeleton, previously performed surgery of the spine, pelvic girdle, or shoulder girdle, pregnancy, advanced spinal deformity due to AS or other disorders precluding an adequate MRI examination, and technical contraindications to MRI such as cardiac pacemakers or similar devices. The same exclusion criteria applied to the control group, supplemented by a questionnaire to rule out symptoms of specific back pain (IBP symptoms as defined above, psoriasis, inflammatory bowel disease, symptoms of radiculopathy or spinal stenosis, previous vertebral fracture or major spinal injury, known osteoporosis, high grade spondylolisthesis, or major spinal deformities such as severe scoliosis). MRI protocol. Imaging was performed with a Siemens Avanto 1.5T magnet (Siemens Medical Solutions, Erlangen, Germany). The system can address up to 18 independent radiofrequency channels so that 6 coils can be plugged into the system simultaneously. For the purpose of this study, 3 coils built into the MRI table were employed (head, neck, and spine coil). Two body matrix coils with 6 elements each were placed on the patient’s chest and abdomen, in addition to a flexible coil placed over the hips in tall patients. Sagittal turbo STIR images of the entire spine and sacrum were acquired with the following parameters: repetition time 6,270 msec, echo time 93 msec, and inversion time 130 msec. The turbo factor was 21, the parallel acquisition technique factor was 2, and the generalized autocalibrating partially parallel acquisition mode was used. The images were obtained in 2 steps with automated combination of the 2 sequences into a single image series. Twenty slices were acquired with a slice thickness of 3– 4 mm and an interslice gap of 0.3– 0.4 mm.
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Figure 1. A, 33-year-old male patient with ankylosing spondylitis (HLA–B27 positive, symptom duration 5 years). The sixth thoracic vertebra displays a lateral inflammatory lesion (LIL) on a STIR sequence in this patient with scoliosis. In this region of the spine, the sagittal slice does not include the spinal canal. In contrast, the spinal canal is displayed in the lumbar spine, which shows 2 anterior corner inflammatory lesions (aCIL) of the first and third lumbar vertebra. B, 31-year-old healthy male control subject. Two vertebral corner STIR signal alterations that meet the definition of a CIL (arrows) were visible in the eighth and tenth thoracic vertebrae on 4 consecutive sagittal slices.
The combined field of view was 780 ⫻ 450 mm, the pixel size was 1.0 ⫻ 1.0 mm, and the acquisition time was 2 ⫻ 2 minutes 49 seconds. MRI analysis. STIR sequences of the entire spine were read and scored independently by 3 readers blinded to patient identifiers and clinical characteristics. Readers did not have access to the coronal SI joint images. Two readers (RAK, WPM) were not involved in clinical assessments, whereas the third (UW) was responsible for the recruitment of patients and healthy volunteers. One reader (WPM) is a member of the Canada/Denmark International MRI Working Group, which developed standardized defi-
nitions for abnormalities of the spine on MRI in SpA. One reader (UW, a rheumatologist) was involved in the initiation of the whole-body MRI in SpA project and was trained by WPM and RGWL during video teleconference sessions that focused on the application of these standardized definitions. The third reader (RAK, a radiologist) participated in a calibration exercise in UW’s institution based on reference cases and on whole-body MRI examples not included in this study. The films were evaluated in random order on electronic work stations in the institution of each reader. The findings were recorded electronically on a separate screen using a Microsoft Excel (Microsoft, Redmond, WA) based
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worksheet containing all possible inflammatory lesions on the x-axis and the 46 vertebral end plates, from the C2 lower end plate to the S1 upper end plate, on the y-axis. Increased STIR signal denoting active inflammation was recorded for the entire spine according to the definitions proposed by the Canada/Denmark International MRI Working Group, as demonstrated in reference images available online at www.arthritisdoctor.ca (7,8). The following specific lesions were recorded in a dichotomous manner (present/absent) (13): vertebral corner inflammatory lesions (CIL; anterior and posterior), vertebral noncorner inflammatory lesions (NIL), lateral inflammatory lesions (LIL), and facet joint or other posterior element inflammatory lesions (FIL/PIL). CIL and NIL are detected in central sagittal slices (slices that include the spinal canal), whereas LIL are detected in lateral slices (slices that do not include the spinal canal) (Figure 1A). FIL/PIL are signal alterations adjacent to a facet joint or in another posterior structure (except the pedicle). Statistical analysis. Prestatistical analysis. Thirteen of 95 whole-body MRIs showed a lumbosacral transitional anomaly, and 2 of 95 MRIs displayed a partial vertebral fusion; the corresponding MRI scoring sheets were adapted accordingly. Only lesions that were scored concordantly between ⱖ2 observers were entered in summary tables of the 3 possible reader pairs. Concordance was defined as a lesion scored concordantly by 2 readers concerning the spinal level as well as the type of inflammatory lesion.
Records of any vertebral end plate with a difference in ⱖ1 inflammatory lesions between a reader pair were regarded as discordant. Discordance was expressed as mean percentage of vertebral end plates with discordant findings in relation to the total of 46 end plates per study subject. Analysis. Concordantly scored inflammatory lesions for the 3 reader pairs comparing 35 patients with AS and 25 patients with IBP versus 35 and 25 healthy sex- and agematched controls were used to compute specificity, sensitivity, and likelihood ratios (LRs) according to the specific type and number of each inflammatory lesion for the entire spine and by spinal segment. For these values, 95% confidence intervals (95% CIs) were computed using the R package epiR (14,15). Standard references were used for the 95% CI formulas for sensitivity and specificity (16) and for LRs (17). No adjustment for multiple testing was done in computation of the 95% CIs. To assess the capacity of each lesion to discriminate between diagnostic categories and to compare the performance of the 3 reader pairs, receiver operating characteristic (ROC) curves and areas under the curve (AUC) were computed (18,19). In general, ROC curves and AUC allow for a comparison of different diagnostic tests based on an ordinal or continuous variable. A nondiscriminative test delivers a diagonal line as an ROC curve, with a corresponding AUC of 0.5. The better the diagnostic quality of a test, the more pronounced the shift of the ROC curve into the upper left corner. The AUC of an ideal ROC curve, which passes through the upper left corner, is 1. This method of presentation does not need to define cutoff
Table 1. Characteristics of the study participants and descriptive data of the inflammatory lesions*
Male:female Age, years Symptom duration HLA–B27 positive, % BASDAI, NRS BASDAI 2, NRS BASFI, NRS BASMI, range 0–10 Nocturnal pain, NRS Lumbar morning stiffness, NRS Intensity Duration ESR (mm/1hour) CRP level‡ CIL§ tCIL§ lCIL§ NIL§ LIL§
AS group
IBP group
Control group
28:7 31.5 (19.3–44.8) 8 years (2.1–29) 91† 4.7 (2.2–7) 7 (4–10) 2.9 (0–7.7) 1 (0–7) 5 (0–10)
18:7 27 (17.3–44.8) 10 months (4–24) 92 4.2 (1.2–7.2) 6 (2–10) 2.2 (0–8.2) 0 (0–4) 7 (0–10)
28:7 30.8 (17.7–44.7) NA NA NA NA NA NA NA
6 (0–10) 3 (0–10) 11 (1–72) 5 (0–150) 1/0/0 (2) 1/0/0 (1–2) 0/0/0 (1) 0/0/0 (0) 0/0/0 (0)
NA NA NA NA 0/0/0 (0–0.5) 0/0/0 (0) 0/0/0 (0) 0/0/0 (0) 0/0/0 (0)
6 (0–10) 4 (0–10) 12 (2–60) 6.5 (1–46) 5/6/5 (8–9.5) 3/4/3 (7.5–8) 1/1/1 (2–2.5) 0/0/0 (0) 0/0/0 (0.5–2)
* Values for patient characteristics are the median (range) unless otherwise indicated. AS ⫽ ankylosing spondylitis; IBP ⫽ inflammatory back pain; NA ⫽ not applicable; BASDAI ⫽ Bath Ankylosing Spondylitis Disease Activity Index (11); NRS ⫽ numeric rating scale; BASDAI 2 ⫽ second item on the BASDAI (reflects back pain); BASFI ⫽ Bath Ankylosing Spondylitis Functional Index (20); BASMI ⫽ Bath Ankylosing Spondylitis Metrology Index (21); ESR ⫽ erythrocyte sedimentation rate; CRP ⫽ C-reactive protein; CIL ⫽ corner inflammatory lesion; tCIL ⫽ thoracic CIL; lCIL ⫽ lumbar CIL; NIL ⫽ noncorner inflammatory lesion; LIL ⫽ lateral inflammatory lesion. † HLA–B27 had not been determined in 1 patient (percentage based on 34 patients with AS). ‡ Reference range
