Rheumatoid arthritis (RA) is characterized by proliferative, hypervascularized synovitis, resulting in bone erosion, damage to cartilage, joint destru

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1 Note: This copy is for your personal, non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at Clarissa Canella, MD Peggy Philippe, MD Vittorio Pansini, MD Julia Salleron, RA René-Marc Flipo, PhD Anne Cotten, PhD Use of Tomosynthesis for Erosion Evaluation in Rheumatoid Arthritic Hands and Wrists1 Purpose: Materials and Methods: To compare tomosynthesis with radiography for the detection of hand and wrist bone erosions in patients with rheumatoid arthritis (RA), using multidetector computed tomography (CT) as the reference method. The study was approved by the local ethics committee, and written consent was obtained from all patients. From December 2008 to April 2009, 30 consecutive patients with RA were included in this prospective study. They underwent radiography, tomosynthesis, and CT of the most symptomatic hand and wrist on the same day. Two radiologists and one rheumatologist independently read images from the three imaging modalities. ORIGINAL RESEARCH n MUSCULOSKELETAL IMAGING Results: A total of 232 erosions were detected with CT, while 199 and 140 erosions, respectively, were detected with tomosynthesis and More erosions were revealed with CT than with tomosynthesis and radiography ( P,.0001); significantly more erosions were shown with tomosynthesis than with radiography ( P,.0001). With CT as the reference method for bone erosions, the overall sensitivity, specificity, and accuracy of tomosynthesis were, respectively, 77.6%, 89.9%, and 83.1%. The corresponding values for radiography were 53.9%, 92%, and 70.9%. The sensitivity of each reader increased by roughly 20% with use of tomosynthesis. Conclusion: The depiction of bone erosions of the hands and wrists is significantly greater with tomosynthesis than with q RSNA, 2010 Supplemental material: /suppl/doi: /radiol /-/dc1 1 From the Department of Musculoskeletal Radiology, Centre de Consultations et d Imagerie de l Appareil Locomoteur (C.C., V.P., A.C.), Department of Rheumatology, Centre André Verhaeghe, Hôpital Roger Salengro (P.P., R.M.F.), and Department of Biostatistics (J.S.), Centre Hospitalier Régional Universitaire de Lille, Rue du Professeur Emilie Laine, Lille 59000, France. Received April 19, 2010; revision requested June 8; revision received July 23; accepted August 11; fi nal version accepted August 12. Address correspondence to C.C. ( clacanella@yahoo.com.br ). q RSNA, 2010 Radiology: Volume 258: Number 1 January 2011 n radiology.rsna.org 199

2 Rheumatoid arthritis (RA) is characterized by proliferative, hypervascularized synovitis, resulting in bone erosion, damage to cartilage, joint destruction, and long-term disability ( 1 3 ). The diagnosis of RA is based on clinical, laboratory, and radiographic findings ( 1 ). Radiography of the hand and wrist is traditionally used for the diagnosis, staging, and follow-up in patients with RA and for the assessment of treatment effectiveness in individual patients ( 4 6 ). The main advantages of radiography are short examination time, low cost, and easy access ( 6 ). However, there are also considerable disadvantages, such as low sensitivity for the detection of bone erosions, especially in patients with early RA ( 7 9 ). In fact, the three-dimensional structure studied is projected onto a two-dimensional image, and the detectability of pathologic findings is therefore limited by the overlapped anatomy. Magnetic resonance (MR) imaging and ultrasonography (US) ameliorate this problem and are thus more accurate for visualizing bone erosions while providing an assessment of Advances in Knowledge n The overall sensitivity, specificity, and accuracy for tomosynthesis of the hand and wrist were 77.6%, 89.9%, and 83.1%, respectively; the corresponding values for radiography were 53.9%, 92%, and 70.9%. n The sensitivity of each reader in the detection of bone erosions in the hand and wrist increased by roughly 20% when using tomosynthesis compared with n The increased sensitivity for tomosynthesis of the hand and wrist was achieved with a fairly small increase in radiation dose compared with n For patients with early rheuma- toid arthritis (RA), the median erosion score was significantly higher with tomosynthesis than with radiography of the hand and wrist. soft-tissue changes ( 7,9 20 ). Multidetector computed tomography (CT) may be even more accurate than MR imaging and US for the detection of bone erosions ( ). Tomosynthesis is a new technique developed from conventional tomography. With conventional tomography, only a single section can be obtained at one time, which requires considerable radiation dose ( 24 ). In tomosynthesis, by collecting a number of projected images at different angles with a digital detector, an unlimited number of section images at arbitrary depths can be reconstructed ( 25 ). As there is less overlapping anatomy on these section images than on projection radiographs, detail detection may be greater ( 26 ). The purpose of this study was to compare tomosynthesis with radiography for the detection of hand and wrist bone erosions in patients with RA, by using multidetector CT as the reference method. Materials and Methods Patients From December 2008 to April 2009, 30 consecutive patients with RA fulfilling the American College of Rheumatology criteria ( 3 ) were included in this prospective study. There were 21 female patients (mean age, 53.4 years; median, 52 years; range, years), and nine male patients (mean age, 47.7 years; median, 47 years; range, years), Implications for Patient Care n Tomosynthesis improves the detection of bone erosions of the hand and wrist in patients with RA. n The use of tomosynthesis of the hand and wrist is associated with a fairly small increase in radiation dose compared with n An earlier detection of bone erosions of the hand and wrist by means of tomosynthesis may have useful therapeutic implications in patients with RA. with a mean disease duration of 7 years 3 months (range, 5 months to 36 years). Twelve patients (40%) had early RA at presentation, defined by presence of the disease for less than 2 years since the first episode of clinically detectable joint inflammation. All patients underwent radiography, tomosynthesis, and CT examinations of the most symptomatic hand and wrist on the same day. The study was approved by the local ethics committee, and written consent was obtained from all patients. Conventional Radiography The digital radiographic examination (Definium 8000; GE Healthcare, Chalfont St Giles, England) included posteroanterior and oblique views of the hand and wrist obtained at a tube voltage of 55 kv and a current of 2 ma, according to the standard protocol of our department. The mean total dose was mgy per patient that is, a mean effective dose of m Sv when using the conver sion factor (0.63) reported by Okkalides and Fotakis ( 27 ). Tomosynthesis The tomosynthesis examinations were performed with a beta version of a commercially available product (Volume RAD; GE Healthcare). Thirty low-dose projection images were collected at a tube voltage of 55 kv and current of 2 ma within 6.4 seconds. The detector posi tion was fixed, whereas the x-ray tube performed a continuous horizontal Published online before print /radiol Radiology 2011; 258: Abbreviation: RA = rheumatoid arthritis Author contributions: Guarantors of integrity of entire study, C.C., P.P., R.M.F., A.C.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of fi nal version of submitted manuscript, all authors; literature research, C.C., P.P., R.M.F., A.C.; clinical studies, C.C., P.P., V.P., R.M.F., A.C.; statistical analysis, C.C., P.P., J.S., R.M.F., A.C.; and manuscript editing, C.C., P.P., R.M.F., A.C. Authors stated no fi nancial relationship to disclose. 200 radiology.rsna.org n Radiology: Volume 258: Number 1 January 2011

3 movement from 2 19 to +19 around the standard orthogonal posteroanterior position. The mean total dose was mgy per patient (ie, a mean effective dose of m Sv) ( 27 ). The examination resulted in 30 reconstructed coronal section images with a nominal thickness of 1 mm without any overlap. CT Examination A wrist and hand CT scan was obtained by using 64-section equipment (Somatom Sensation 64; Siemens, Forchheim, Germany). The patient was positioned prone with the dominant arm outstretched, palm facing downward. All exposures were standardized according to the standard protocol used in our department (120 kv and 136 ma, on average). Axial sections 0.6 mm thick were obtained, and these were used to reconstruct sagittal, coronal, and axial images 1 mm thick. The scoring of CT scans was performed on the 1-mm sections. The mean dose-length product was 315 mgy cm (range, mgy cm). Image Evaluation Preliminary training and standardization were performed for each technique. Images from the three modalities were then read independently by three readers: two musculoskeletal radiologists (A.C. and C.C.) and one rheumatologist (P.P.), with, respectively 17, 3, and 8 years of experience in the radiologic assessment of arthritis. The most experienced radiologist (A.C.) performed a second reading of the three imaging modalities for the assessment of intraobserver agreement. The time elapsing between the two readings was greater than 3 months. The readers were blinded to clinical and imaging modalities (imaging modalities performed on the same day as well as prior images). Images obtained at radiography, tomosynthesis, and CT were separated according to imaging modality in three different groups of patients randomly assigned to each group. The three readers independently and consecutively read the radiographic, tomosynthesis, and CT images with a 3 4 week interval between each imaging modality group. Each of the readers evaluated all the images for the presence and grade of bone erosions at the wrists and metacarpophalangeal and proximal interphalangeal joints by using software (RA 600; GE Healthcare) designed to display medical images. The observers were, however, allowed to change window width and level and to use the pan and zoom functions. The principles of the Sharp van der Heijde scoring method for the assessment of wrist and hand radiographs and tomosynthesis images were applied, with an erosion score ranging from 0 to 5 assigned to 14 areas ( ). Erosions were characterized as a bone defect with an interrupted cortical bone ( 35,36 ). Individual erosions were given a score of 1 when discrete, a score of 2 if larger, and a score of 3 when the erosion extended over the imaginary middle of the bone. If there was more than one erosion present in a single bone, the individual erosion scores were summed up (with a maximum of five points allowed for each joint according to the scoring method used). For the CT images, erosions were assessed by using axial, coronal, and sagittal reformations with the same criteria as for the radiographic and tomosynthesis images. Erosions on CT images were defined as a sharply demarcated area of focal bone loss seen in two planes, with a cortical break (loss of cortex) seen in at least one plane. They were scored according to the principles of the method described above. The total erosion score for a single wrist and hand ranged from 0 to 70. Statistical Analysis All statistical analysis was performed by using statistical software (SAS; SAS Institute, Cary, NC). Continuous data were expressed as mean and standard deviation or as median and interquartile range, as appropriate. Qualitative data were expressed as frequency and percentage. P,.05 was considered to indicate a statistically significant difference. Comparison of the age between male and female patients was performed by using the Mann-Whitney U test. Interobserver and intraobserver agreement for each imaging method was assessed by using the intraclass correlation coefficient according to the Fleiss method. A value greater than 0.8 was taken as constituting good agreement ( 37 ). For further analysis, only one reader was taken into account. CT was the reference method. To study the sensitivity, specificity, and accuracy of tomosynthesis and radiography compared with CT, the statistical unit was the area. For each area, the presence or absence of erosion was encoded by a binary variable (presence of an erosion defined as having an erosion score of 1 or higher). There were 14 areas per patient and 30 patients, and therefore 420 statistical units. Sensitivities were compared by using the McNemar test. Paired comparisons of the erosion scores according to the imaging method were performed by using paired t tests or paired Wilcoxon signed-rank test. Results There was no significant difference in age between male and female patients ( P =.0732). Radiographic, tomosynthesis, and CT images could be scored in each patient. The interobserver (respectively: , , and ) and intraobserver (respectively: , , and ) reliability for bone erosions at independent scoring was excellent, regardless of the imaging modality used. A total of 232 erosions were detected with CT, while 199 and 140 erosions were detected with tomosynthesis and radiography, respectively ( Table ) ( Figs 1, 2, E1, E2 [online]). CT revealed more erosions than did tomosynthesis and radiography ( P,.0001); tomosynthesis showed significantly more erosions than did radiography ( P,.0001). With CT as the reference method for bone erosions, the overall sensitivity, specificity, and accuracy of tomosynthesis was, respectively, 77.6%, 89.9%, and 83.1%. The corresponding values for radiography were 53.9%, 92%, and 70.9%. The sensitivity of each reader increased by roughly 20% when using tomosynthesis ( P,.0001). The mean erosion score ( 6 standard deviation) per patient was (range, 4 70) with CT, Radiology: Volume 258: Number 1 January 2011 n radiology.rsna.org 201

4 Figure 1 Figure 1: Images obtained in a 58-year-old woman with RA show two erosions (arrows) in the radial aspect of the second and third proximal phalanges on (a) anteroposterior radiograph, (b) a sequence of three tomosynthesis images, and (c, e) coronal and (d) axial reformations from multidetector CT. Note that both erosions can be better visualized with tomosynthesis than with Number of Erosions, Erosion Scores, and Sensitivity, Specificity, and Accuracy of Imaging Methods Parameter Radiography Tomosynthesis CT Total no. of erosions Mean score per patient * Median score 7.5 (2 18) 14 (5 25) 18.5 (6 31) Sensitivity (%) Specifi city (%) Accuracy (%) * Data are mean 6 standard deviation. Data in parentheses are the interquartile range (range, 1 66) with tomosynthesis, and (range, 0 66) with The mean score was significantly higher with tomosynthesis than with radiography ( P,.0001) and significantly higher with CT than with tomosynthesis ( P,.0001). For patients manifesting early RA ( n = 12), the median erosion score was 2.5 (range, 1 6.5) with radiography, 4 (range, 2 13) with tomosynthesis, and 6 (range, 5 16) with CT. The median score was significantly higher with tomosynthesis than with radiography ( P =.0010) and significantly higher with 202 radiology.rsna.org n Radiology: Volume 258: Number 1 January 2011

5 Figure 2 Figure 2: Images obtained in a 63-year-old man with RA show three erosions (arrows) of the second metacarpophalangeal joint (two at the basis of the proximal phalanx and one on the radial aspect of the metacarpal bone) on (a) anteroposterior radiograph, (b) a sequence of four tomosynthesis images, and (c) a coronal reformation from multidetector CT. The erosions are much better identifi ed with tomosynthesis than with CT than with tomosynthesis ( P =.0010). Two of these patients had scores of 0 with radiography, 2 with tomosynthesis, and 5 and 6 with CT. Discussion Resulting from proliferative synovitis, bone erosion represents the defining pathologic feature of RA ( 1 3 ). The majority of erosions develop during the first 2 years of the disease, and during the first 6 months in patients with aggressive disease ( 38 ). The presence of bone erosions in early RA typically requires administration of disease-modifying antirheumatic drug therapy, or DMARD, with the aim of delaying and, in some cases, preventing the progression of RA ( 1,36 ). During the follow-up, a precise evaluation of the number and extent of the erosions is essential to measure the effect of treatment. A progression of the erosive process would require therapeutic changes ( 2,6,39 ). Therefore, the use of erosion scoring aims mainly at detecting either the first erosions (for diagnostic purposes) or the earliest change in the size or number of erosions (to assess the effectiveness of treatment). The bone images obtained at radiography, tomosynthesis, and CT depend on the attenuation of the x-ray beam, owing to the tissue density. Several authors have reported that multidetector helical CT represents the best imaging modality for the assessment of bone erosions in RA patients ( ). Indeed, the multiplanar capacity of this technique and the enhanced cortical definition that it provides allow a much better assessment of complex anatomic regions, such as the carpus, than radiography ( 40,44 ). The higher sensitivity of CT compared with radiography was also confirmed by this study. However, some drawbacks of CT, including higher costs, more limited access, and higher radiation dose than with tomosynthesis and radiography ( 8,15,23,26 ) probably explains, at least in part, why this technique is not routinely performed in RA patients. In fact, according to the international recommendations of the American College of Rheumatism and the European League Against Rheumatism, radiography remains the reference method for the diagnosis and follow-up of patients with RA ( 6,45 49 ). Tomosynthesis may represent an interesting alternative for the evaluation of bone erosions, since in our study it demonstrated a higher sensitivity than radiography, even in patients with early RA. This higher sensitivity is readily understandable, as the technique provides thin coronal sections that allow good bone analysis, in contrast to the three-dimensional projection of bone structures onto a two-dimensional radiograph. The higher sensitivity of CT compared with tomosynthesis is probably due to the possibility of obtaining sagittal and axial images, which are not available with tomosynthesis. As tomosynthesis significantly increases the sensitivity of bone erosion depiction, this new technique may be helpful in addition to or as a substitute for hand radiography in RA patients. However, these preliminary results need to be confirmed by further studies, and the position of tomosynthesis in the assessment of patients with RA remains to be defined. It is important to note, moreover, that the false-positive erosion score was similar for tomosynthesis and radiography (10.1% vs 8% respectively); this may lead to unnecessary drug administration. However, these false-positive findings were mostly located in the interphalangeal joints, Radiology: Volume 258: Number 1 January 2011 n radiology.rsna.org 203

6 14. Haavardsholm EA, Bøyesen P, Østergaard M, Schildvold A, Kvien TK. Magnetic resowhich demonstrate a propensity for microdamage in normal elderly subjects ( 50 ). It might be useful to assess whether this false-positive score would prove similar in a large series of patients with early RA. Differences in hand and wrist radiation may not be a major factor when choosing between these three imaging modalities. The effective doses administered with radiography and tomosynthesis are exceedingly low compared with natural irradiation (2 3 msv/year). The effective dose resulting from CT proved difficult to evaluate due to the lack of reliable conversion coefficients for the hand and wrist published in literature. However the CT dose is probably higher than the dose from radiography by the same factor as for other anatomic regions. This means that the use of tomosynthesis can allow better erosion detection with a fairly small increase in radiation dose. We acknowledge that our study has several limitations. First, only a small number of patients were included. Second, we did not assess the usefulness of tomosynthesis for the depiction of erosions of the feet. This assessment might be useful, as the metatarsophalangeal joints are frequently affected at an early stage in these patients. In conclusion, more bone erosions of the hands and wrists in RA patients can be depicted with tomosynthesis than with Further studies must now be performed to assess the usefulness of tomosynthesis in the early diagnosis of RA and in the evaluation of the progression of the disease during treatment on the basis of the smallest detectable difference. Acknowledgments: The authors express their gratitude to Betty Marchand, Sébastien Boudart, Rémy Klausz, Gerhard Brunst, Thomas Portolan, Pierre Meurin, and Philippe Dupont for their assistance. References 1. Sommer OJ, Kladosek A, Weiler V, Czembirek H, Boeck M, Stiskal M. 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