Sonographic Evaluation of Subclinical Entheseal Involvement in Patients With Behçet Disease

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1 Musculoskeletal Imaging Original Research Ozkan et al. Ultrasound of Enthesopathy in ehçet Disease Musculoskeletal Imaging Original Research Fuat Ozkan 1 Gozde Yildirim Cetin 2 etul akan 3 Ali Murat Kalender 4 Murvet Yuksel 1 Hasan Cetin Ekerbicer 5 Mehmet Sayarlioglu 2 Ozkan F, Cetin GY, akan, et al. Keywords: ehçet disease, enthesopathy, ultrasound DOI: /AJR Received January 17, 2012; accepted after revision April 13, Department of Radiology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Yörükselim mah. Hastane cad. No. 32, Kahramanmaras, Turkey. Address correspondence to F. Ozkan (drfozkan@yahoo.com). 2 Department of Rheumatology, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey. 3 Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey. 4 Department of Orthopaedic Surgery, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey. 5 Department of Public Health, Faculty of Medicine, Kahramanmaras Sutcu Imam University, Kahramanmaras, Turkey. WE This is a Web exclusive article. AJR 2012; 199:W723 W X/12/1996 W723 American Roentgen Ray Society Sonographic Evaluation of Subclinical Entheseal Involvement in Patients With ehçet Disease OJECTIVE. The aim of the current study was to determine the prevalence of subclinical entheseal involvement in patients with ehçet disease via ultrasound using a newly developed method, the Madrid sonography enthesitis index. SUJECTS AND METHODS. The study was conducted with 36 patients with ehçet disease and 46 healthy sex- and age-matched control subjects. All patients with ehçet disease who had no clinical evidence of arthritis or enthesitis underwent an ultrasound examination. All sonographic findings were identified according to the Madrid sonography enthesitis index. Madrid sonography enthesitis index values of patients and control subjects were compared by Student t test and Mann-Whitney U test. Validity was analyzed by receiver operating characteristic curve. RESULTS. Total enthesitis score was ± 6.16 among patients with ehçet disease and 2.06 ± 2.18 among healthy control subjects (p < 0.001). The receiver operating characteristic curve established an ultrasound score greater than 4.5 in the ehçet disease group as the best cutoff point differentiating case subjects from control subjects. This cutoff was exceeded by 88.8% of the patients with ehçet disease. When the Madrid sonography enthesitis index score in each affected enthesis was evaluated, patients with ehçet disease had significantly higher scores than did control subjects when all entheseal sites were compared (all p values < 0.05). CONCLUSION. This is the first study to our knowledge to show significant subclinical enthesopathy of the triceps tendon enthesis in patients with ehçet disease who had no arthritic involvement. These data suggest that the Madrid sonography enthesitis index scoring system for sonographic detection of enthesopathy should be incorporated into the clinical protocol for evaluating patients with ehçet disease in routine clinical practice. ehçet disease (D) is a chronic disorder with multisystemic involvement. Musculoskeletal involvement is one of the most frequent clinical manifestations of D [1]. Several authors have considered that D could be classified within the spondyloarthropathy complex because of some common features, especially in a subgroup of patients with D with acneassociated arthritis [2, 3]. Enthesitis is an important characteristic feature of the spondyloarthropathies. Although there is great variation of the entheseal involvement (3.4 38%) in patients with D, the exact percentage is unclear [4, 5]. Little is known about the prevalence of entheseal involvement in patients with D who do not have arthritis [3]. Recently, the development of high-resolution ultrasound transducers has made it possible to assess enthesitis more accurately through sonography than clinical examination. Several reports [3, 6, 7] have described the use of ultrasound in identifying the features of lower limb enthesitis by using the Glasgow ultrasound enthesitis scoring system (GUESS). Recently, a new ultrasound enthesis score has been developed the Madrid sonography enthesitis index (MASEI) that contains additional parameters beyond those used by GUESS, including power Doppler and upper limb examinations [8]. The aims of the current study were to determine the prevalence of subclinical entheseal involvement in patients with D by using MASEI and to evaluate the correlation between MASEI score and other clinical parameters in patients with D. Subjects and Methods The study consisted of 36 patients with D (16 women and 20 men; mean age, 33.8 ± 7.45 years) who met the criteria of the International Study W723

2 Ozkan et al. Group for ehçet s Disease [9] and 46 healthy sex- and age-matched control subjects (22 women and 24 men; mean age, 30.1 ± 5.57 years). Patients with D consecutively admitted to our hospital and healthy control subjects both underwent a clinical examination by two expert rheumatologists who recorded tenderness elicited by pressure and contraction against resistance of the corresponding entheses to confirm the absence of entheseal involvement. Subsequently, patients and healthy subjects without any clinical evidence of enthesitis underwent an ultrasound examination. Exclusion criteria were as follows: clinical evidence of arthritis in the D group; younger than 18 years; peripheral neuropathy of upper or lower limbs; history of recent severe trauma at entheses scanned; history of knee, ankle, or elbow surgery; and history of corticosteroid injection of the examined structures. The study was conducted in patients who came from the outpatient clinic of rheumatology of our university hospital. This study was approved by the local ethics committee of our hospital. Furthermore, the examination was explained to the patients and control subjects, and written informed consent was obtained. All ultrasound examinations were performed in a darkened room by an experienced radiologist trained in musculoskeletal sonography who was blinded to clinical data. Ultrasound examinations were performed using a MyLab 70 XVG (Esaote iomedica) equipped with a 6- to 18-MHz broadband linear transducer (Fig. 1). Abnormalities were quantified using the MASEI score [8], which systematically explores six enthesis locations bilaterally (namely, proximal plantar fascia, distal Achilles tendon, distal and proximal patellar ligaments, distal quadriceps, and brachial triceps tendons) in each patient (Table 1). Multiplanar ultrasound examinations of the quadriceps and patellar entheses were performed with the patient in the supine position with the knees flexed 30. For the examination of the Achilles tendon and the proximal plantar aponeurosis, the patient was in the prone position with the feet hanging over the edge of the examination table at 90 of flexion. Triceps tendon entheses were evaluated while the subjects were seated in front of the examiner, with the shoulders in internal rotation and elbows flexed 90. The ultrasound exploration evaluated the following elemental lesions of enthesis at each site: thickness, structure, calcifications, bursae, erosions, and power Doppler signal in bursa or enthesis full tendon (cortical bone profile, intratendon, and paratendon on the enthesis insertion) [8]. Meticulous effort was made to ensure that the scanning planes were parallel to the tendon fibers, to avoid acoustic fiber anisotropy. Thicknesses of ligaments, fascia, and tendons were measured on the axial scan as the maximum anteroposterior diameter in millimeters, disregarding the paratendon at the point of maximum thickness proximal to the bony insertion. Structure was defined as pathologic if loss of fibrillar pattern, hypoechoic aspect, or fusiform thickening of the enthesis occurred (Fig. 2); bone erosion was defined as a cortical interruption with a step-down contour defect; and enthesophyte was defined as a step-up bony prominence at the end of normal bone profile (Figs. 3 6). Calcifica- TALE 1: Madrid Sonographic Enthesis Index (MASEI) Scoring System Data Value Inferior pole of the calcaneus: plantar aponeurosis enthesis Plantar aponeurosis structure 0 or 1 Plantar aponeurosis thickness > 4.4 mm 0 or 1 Inferior pole of calcaneus erosion 0 or 3 Inferior pole of calcaneus enthesis calcification 0, 1, 2 or 3 Plantar aponeurosis enthesis power Doppler signal 0 or 3 Superior pole of the calcaneus: Achilles tendon enthesis Achilles tendon structure 0 or 1 Achilles tendon thickness > 5.29 mm 0 or 1 Retrocalcaneal bursitis 0 or 1 Posterior pole of calcaneus erosion 0 or 3 Posterior pole of calcaneus enthesis calcification 0, 1, 2, or 3 Posterior pole of calcaneus power Doppler signal 0 or 3 Tibial tuberosity: distal patellar ligament enthesis Patellar ligament structure 0 or 1 Patellar ligament thickness > 4 mm 0 or 1 Infrapatellar bursitis 0 or 1 Tibial tuberosity erosion 0 or 3 Tibial tuberosity enthesis calcification 0, 1, 2, or 3 Tibial tuberosity enthesis power Doppler signal 0 or 3 Inferior pole of the patella: proximal patellar ligament enthesis Patellar ligament structure 0 or 1 Patellar ligament thickness > 4 mm 0 or 1 Inferior pole of patella erosion 0 or 3 Inferior pole of patella enthesis calcification 0, 1, 2, or 3 Inferior pole of patella enthesis power Doppler signal 0 or 3 Superior pole of the patella: quadriceps tendon enthesis Quadriceps tendon structure 0 or 1 Quadriceps tendon thickness > 6.1 mm 0 or 1 Superior pole of patella erosion 0 or 3 Superior pole of patella enthesis calcification 0, 1, 2, or 3 Superior pole of patella enthesis power Doppler signal 0 or 3 Olecranon tuberosity: triceps tendon enthesis Triceps tendon structure 0 or 1 Triceps tendon thickness > 4.3 mm 0 or 1 Olecranon erosion 0 or 3 Olecranon enthesis calcification 0, 1, 2, or 3 Olecranon enthesis power Doppler signal 0 or 3 Note Each item scores one point, except for calcification (0, 1, 2, or 3) and erosion and Doppler signal (0 or 3). Maximum possible total score on both sides (12 entheses) is 136. W724

3 Ultrasound of Enthesopathy in ehçet Disease TALE 2: Demographic Data and Results of the Madrid Sonography Enthesitis Index (MASEI) Score Parameter ehçet Group Control Group Subjects Sex ratio (women to men) 16:20 22:24 Age (y) (mean ± SD) 33.8 ± ± 5.57 Age range (y) MASEI score (mean ± SD) Men 11.1 ± 1.2 a 2.29 ± 0.45 Women 13.5 ± 1.74 a 1.81 ± 0.45 Overall ± 6.16 a 2.06 ± 2.18 a p < (compared with control subjects). TALE 3: Madrid Sonography Enthesitis Index (MASEI) Scores by Enthesis Affected Enthesis Affected ehçet Group Control Group Triceps tendon 2.41 ± 2.32 a 0.02 ± 0.14 Quadriceps tendon 1.83 ± 2.29 a 0.15 ± 0.46 Proximal patellar tendon 1.27 ± 1.64 b 0.28 ± 0.5 Distal patellar tendon 1.5 ± 1.68 a 0.28 ± 0.58 Achilles tendon 4.27 ± 3.13 a 1.04 ± 1.63 Plantar fascia 0.94 ± 1.52 c 0.28 ± 0.93 Note Data are mean ± SD MASEI score. a p = (compared with control subjects). b p = (compared with control subjects). c p = (compared with control subjects). TALE 4: Tendon or Aponeurosis Thickness Measurements on the Nondominant Extremities, by Group Enthesis Affected ehçet Group Control Group Triceps tendon 3.77 ± 0.68 a 3.04 ± 0.29 Quadriceps tendon 5.9 ± 0.73 b 5.4 ± 0.51 Proximal patellar tendon 4.2 ± 0.39 a 3.52 ± 0.42 Distal patellar tendon 4.23 ± 0.62 a 3.65 ± 0.47 Achilles tendon 4.4 ± 0.65 c 3.94 ± 0.53 Plantar fascia 3.26 ± 0.7 b 2.85 ± 0.38 Note Data are mean ± SD thickness, in millimeters. a p = (compared with control subjects). b p = (compared with control subjects). c p = (compared with control subjects). tions were evaluated at the area of the enthesis insertion and classified according to size (Fig. 7); for simplicity, ossifications and enthesophytes at the enthesis were also included as calcifications. lood flow was examined in each enthesis using power Doppler ultrasound, the settings of which were standardized with a pulse repetition frequency of 750 Hz, a Doppler frequency between 8.3 and 11.1 MHz, and a low wall filter (Fig. 8). Meticulous effort was made to avoid compressing the tissues under examination to prevent blanching of power Doppler signal due to the transducer pressure [7]. The MASEI score is a weighted score, previously calculated by logistic regression, that overestimates the score of three elemental lesions calcification (0 3), Doppler (0 or 3), and erosion (0 or 3) while scoring tendon structure, tendon thickness, and bursa as either a 0 or a 1 (Table 1). Calcifications were scored as 0 if not present or as 1 if a small calcification or an ossification with an irregularity of enthesis cortical bone profile was seen. Calcifications were scored as 2 if there was obvious presence of enthesophytes (hyperechoic spurs forming at a tendon insertion into bone, growing in the direction of the natural pull of the tendon involved), or if medium-sized calcifications or ossifications were seen. Last, they were scored as 3 if large calcifications or ossifications were present. Total MASEI score was calculated as the sum of scores for both sides (12 entheses), with a maximum possible score of 136 [8]. In the statistical analysis, quantitative data were expressed as the mean ± SD and range, and qualitative data were expressed as percentages. Student t test and Mann-Whitney U test were used for comparison of patient and control groups. Pearson correlation coefficient was used for the analysis of correlation. A receiver operating characteristic curve was used to calculate the different levels of sensitivity and specificity at every cutoff point. The statistical significance was set at p < 0.05 throughout. Results The demographic characteristics and mean ± SD MASEI score for patients and control subjects are shown in Table 2. The mean value of the MASEI scores between groups achieved statistical significance (p < 0.001). Table 3 shows the MASEI score in each enthesis affected. Patients with D had significantly higher mean ± SD scores than did control subjects when all entheseal sites were compared (all p values < 0.05). There were no statistically significant differences among MASEI scores between different subgroups of patients with D who had chronic disease related features, including oral or genital aphthous lesions, uveitis, and vasculitic complications. The mean disease duration was 71.5 ± 12.1 months for patients with D. No statistically significant correlation was found between the MASEI score and the D duration (r = 0.00, p = 0.984). The area under the receiver operating characteristic curve was 0.95 (95% CI, ). The cutoff point of 4.5 had sensitivity of 88.9%, specificity of 87%, positive predictive value of 84.2%, and negative predictive value of 90.9%. As a result, a score greater than 4.5 in patients with D was established as the best cutoff point differentiating case subjects from control subjects. This cutoff point was exceeded by 88.8% of the patients with D and only 13% of the subjects in the control group. A total of 432 entheseal sites in 36 patients with D were examined using ultrasound. The highest number of elemental lesions of entheseal sites was seen for calcification (78/432, 18.1%), followed by thickness (61/432, 14.1%), erosion (40/432, 9.3%), bursitis (26/432, 6.0%) structure (15/432, 3.5%), and power Doppler ultrasound (10/432, 2.3%). W725

4 Ozkan et al. The comparative tendon thickness measurements are shown in Table 4. The mean tendon thickness was greater for patients with D than for control subjects (all p values < 0.05). Discussion Enthesitis is a characteristic feature of the spondyloarthropathies and has been regarded as the primary lesion in such diseases [8]. ecause radiography and physical examination are not sensitive enough for the detection of early signs of entheseal involvement [1, 3], high-resolution ultrasound is widely used as an imaging technique in the diagnosis of enthesopathy [10]. Its sensitivity in the determination of enthesitis has been shown in patients with spondyloarthropathy [8, 11, 12]. Subclinical entheseal involvement in patients with D is not clearly recognized. Therefore, we decided to investigate the ability of the MASEI scoring system to identify entheseal involvement in patients with D who did not have any clinical signs of musculoskeletal system involvement. A similar study has been recently conducted by Hatemi et al. [3] using GUESS, which does not include power Doppler evaluation and upper limb enthesis parameters. Although Hatemi et al. added power Doppler ultrasound examination to their evaluation, GUESS still is lacking in several respects in the evaluation of entheseal sites in patients with D. First, in this scoring system, only lower limb entheseal sites were evaluated, and possible mechanical loading on these limbs may influence the entheseal sites [13]. Therefore, triceps tendon enthesis has been added in the MASEI scoring system, because the olecranon has been affected in 60% of patients with spondyloarthropathy [8]. Moreover, Gökoğlu et al. [14] stated that hand tendons were affected in patients with D. We concluded that triceps tendon enthesis scores of patients with D are remarkably higher (p = 0.000) than healthy subjects. This is the most important finding of our study, and it not only suggests that D may warrant inclusion in spondyloarthropathy disease complex but also shows the usefulness of the MASEI scoring system. Second, GUESS evaluates tendon and ligaments only in terms of thickness without taking into account the structural changes. As alint et al. [15] also emphasized, this may lead to underestimation of enthesitis [3]. y contrast, MASEI has scoring parameters that take into account the structural aspects of the enthesis (loss of fibrillar pattern, hypoechoic aspect, and fusiform thickening) [8]. Hatemi et al. [3] accentuated that underestimation of enthesitis due to structural changes would be valid for all groups and thus would not affect their conclusions. However, in our study, patients with D had significantly higher scores than control subjects in terms of structural changes (p = 0.000). Tendon thicknesses were evaluated in patients with D as a part of the MASEI scoring system. We observed that all tendons of D patients were thicker than normal, perhaps owing to the ongoing underlying inflammatory process. Similar findings were reported by Gökoğlu et al. [14]. The MASEI scores were not homogeneously distributed in the six entheses examined (Table 3). Higher scores were found more frequently at the Achilles tendon enthesis, whereas relatively low scores were found at the plantar aponeurosis enthesis, which may be associated with local anatomic and mechanical factors. For example, the existence of higher thicknesses of both skin and subcutaneous tissue overlying the plantar fascia may decrease the sensitivity of ultrasound. The increased frequency of enthesopathy among patients with D who have acne and arthritis compared with patients with D who did not have arthritis has been shown in the literature [3]. However, our results indicate that patients with D who did not have arthritis had higher MASEI scores than age- and sexmatched healthy control subjects. These results suggest a probable association between D and spondyloarthropathy. Although several studies [3, 16] have reported a relationship between these diseases, further research is needed to elucidate this relationship. A limitation of our study is not matching the study population for body mass index, a factor that might influence the enthesis score. Nevertheless, in our study, we did not detect clear differences in body mass index between case and control subjects. In conclusion, this is the first study to show significant subclinical enthesopathy in the triceps tendon enthesis in patients with D who had no arthritic involvement. Our data suggest that the MASEI scoring system for detection of enthesopathy should be incorporated into the clinical protocol for evaluation of patients with D in routine clinical practice. References 1. icer A. Musculoskeletal findings in ehcet s disease. Patholog Res Int 2012; 2012:653, Diri E, Mat C, Hamuryudan V, Yurdakul S, Hizli N, Yazici H. Papulopustular skin lesions are seen more frequently in patients with ehçet s syndrome who have arthritis: a controlled and masked study. Ann Rheum Dis 2001; 60: Hatemi G, Fresko I, Tascilar K, Yazici H. Increased enthesopathy among ehçet s syndrome patients with acne and arthritis: an ultrasonography study. Arthritis Rheum 2008; 58: Chang HK, Lee DH, Jung SM, et al. The comparison between ehçet s disease and spondyloarthritides: does ehçet s disease belong to the spondyloarthropathy complex? J Korean Med Sci 2002; 17: Yurdakul S, Yazici H, Tüzün Y, et al. The arthritis of ehçet s disease: a prospective study. Ann Rheum Dis 1983; 42: Kerimoglu U, Hayran M, Ergen F, Kirkpantur A, Turgan C. Sonographic evaluation of entheseal sites of the lower extremity in patients undergoing hemodialysis. J Clin Ultrasound 2007; 35: Gutierrez M, Filippucci E, De Angelis R, et al. Subclinical entheseal involvement in patients with psoriasis: an ultrasound study. Semin Arthritis Rheum 2011; 40: de Miguel E, Cobo T, Muñoz-Fernández S, et al. Validity of enthesis ultrasound assessment in spondyloarthropathy. Ann Rheum Dis 2009; 68: International Study Group for ehçet s Disease. Criteria for diagnosis of ehçet s disease. Lancet 1990; 335: Falsetti P, Acciai C, Lenzi L, Frediani. Ultrasound of enthesopathy in rheumatic diseases. Mod Rheumatol 2009; 19: de Miguel E, Muñoz-Fernández S, Castillo C, Cobo- Ibáñez T, Martín-Mola E. Diagnostic accuracy of enthesis ultrasound in the diagnosis of early spondyloarthritis. Ann Rheum Dis 2011; 70: de Miguel E, Cobo T, Muñoz-Fernández S, Falcao S, Steinerova M, Martín-Mola E. Value of ultrasound exploration of enthesis in the diagnostic classification of the spondyloarthropathies: development of Madrid sonography enthesitis index (MASEI). Ann Rheum Dis 2007; 66(suppl 2): Mariotti V, Facchini F, Giovanna elcastro M. The study of entheses: proposal of a standardised scoring method for twenty-three entheses of the postcranial skeleton. Coll Antropol 2007; 31: Gökoğlu F, Ceceli E, Ramadan SU, Yorgancioglu ZR, Koşar U. Ultrasonographic evaluation of hand and foot tendons in ehçet s disease. Arch Med Res 2008; 39: alint PV, Kane D, Wilson H, McInnes I, Sturrock RD. Ultrasonography of entheseal insertions in the lower limb in spondyloarthropathy. Ann Rheum Dis 2002; 61: orman P, Gökoğlu F, Taşbaş O, Yilmaz M, Yorgancioğlu ZR. Familial Mediterranean fever related spondyloarthropathy. Singapore Med J 2009; 50:e116 e119 W726

5 Ultrasound of Enthesopathy in ehçet Disease Fig. 1 Sonographic imaging of normal entheseal insertions on longitudinal scan. Fibrillar echotexture of tendons is indicated by calipers or arrowheads. A, Sonogram shows triceps tendon (TT). O = olecranon., Sonogram shows quadriceps tendon (QT). P = patella. C, Sonogram shows proximal patellar ligament (PP). P = patella. D, Sonogram shows distal patellar ligament (DP). T = tibia. E, Sonogram shows Achilles tendon (AT). C = calcaneus, K = Kager fat pad. F, Sonogram shows plantar aponeurosis (PA). C = calcaneus, ST = subcutaneous soft tissue. A C E D F Fig year-old man with structural changes of distal patellar ligament (DP). Longitudinal sonogram shows fusiform thickening at entheseal site (arrowheads). T = tibia. W727

6 Ozkan et al. Fig year-old woman with erosion of triceps tendon (TT) enthesis. O = olecranon. A, Transverse sonogram shows erosion (arrow)., Longitudinal sonogram shows erosion (arrow). A Fig year-old man with erosion of Achilles tendon (AT) enthesis. Longitudinal sonogram of Achilles tendon shows erosion (arrow) at entheseal site. C = calcaneus. Fig year-old woman with erosion of plantar aponeurosis (PA) enthesis. Longitudinal sonogram shows erosion (arrow) at entheseal site. Thickness of plantar fascia was measured between calipers. C = calcaneus. Fig year-old man with erosion of quadriceps tendon (QT) enthesis. Transverse sonogram of distal QT shows erosion (arrow) at superior pole of patella (P). W728

7 Ultrasound of Enthesopathy in ehçet Disease Fig year-old woman with calcification of triceps tendon (TT) enthesis. O = olecranon. A, Transverse sonogram shows calcifications (arrows)., Longitudinal sonogram shows calcifications (arrows). A Fig year-old man with abnormal Doppler signal and erosion of triceps tendon enthesis. Longitudinal sonogram of triceps tendon (TT) shows abnormal Doppler signal (arrow) and erosion (arrowhead) at entheseal site. O = olecranon. W729