The value of contrast-enhanced color doppler ultrasound in the detection of vascularization of finger joints in patients with rheumatoid arthritis.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 46, No. 3, March 2002, pp 647–653 DOI 10.1002/art.10136 © 2002, American College of Rheumatology The Value of Contrast-Enhanced Color Doppler Ultrasound in the Detection of Vascularization of Finger Joints in Patients With Rheumatoid Arthritis Andrea Klauser,1 Ferdinand Frauscher,2 Michael Schirmer,1 Ethan Halpern,2 Leo Pallwein,1 Manfred Herold,1 Gernot Helweg,1 and Dieter ZurNedden1 Objective. A prospective study was performed to assess the usefulness of contrast-enhanced color Doppler ultrasound (CDUS) in the evaluation of intraarticular vascularization of finger joints in patients with rheumatoid arthritis (RA). Methods. We investigated 198 finger joints in 46 patients with RA, and 80 finger joints in 10 healthy volunteers. Joints with varying levels of clinical activity of inflammation were classified as being active, moderately active, or inactive. CDUS was performed with a high-frequency multi-D linear array transducer. A microbubble-based ultrasound (US) contrast agent (Levovist; Schering, Berlin, Germany) was intravenously infused. Doppler findings were rated on the basis of both unenhanced and contrast-enhanced CDUS images. Results. Healthy joints showed no intraarticular vascularization on either unenhanced or contrastenhanced CDUS. Unenhanced CDUS detected intraarticular vascularization in 7 (8%) of 83 inactive joints, in 31 (52%) of 60 moderately active joints, and in 32 (58%) of 55 active joints. Contrast-enhanced CDUS detected intraarticular vascularization in 41 (49%) of 83 joints with inactive RA, in 59 (98%) of 60 joints with moderately active RA, and in all 55 joints with active RA. Detection of intraarticular vascularization was improved by administration of the microbubble-based US contrast agent (P < 0.001). Contrast-enhanced CDUS demonstrated differences in intraarticular vascularization between joints with inactive RA and those with active RA (P < 0.001), between joints with inactive RA and those with moderately active RA (P < 0.001), and between joints with moderately active RA and those with active RA (P < 0.001). Conclusion. The use of a microbubble-based US contrast agent significantly improved the detection of intraarticular vascularization in the finger joints of patients with RA. This technique seems to be a useful adjunct in the assessment of disease activity. A crucial event in the pathogenesis of rheumatoid arthritis (RA) is the development of pannus (1). Proliferation of pannus is an early event in the course of the disease and can be seen before destruction of cartilage and bone. Vascularization of pannus appears to be crucial to its invasive and destructive behavior (2,3). Radiography is currently the method used for assessing the degree of actual joint destruction (4). Contrastenhanced magnetic resonance imaging (MRI) has also been utilized for this purpose, but this technique is not yet routinely available and is relatively cost-intensive and time-consuming (5,6). Hypervascularization of the pannus is usually caused by inflammatory activity. Color Doppler ultrasound (CDUS) imaging allows for detection of vascularity (6–11). CDUS combines the imaging capabilities of conventional B-mode ultrasound (US) with the bloodflow determinations of Doppler US and permits assessment of both the anatomy and the characteristics of blood flow of the vessels at specific sites. However, this technique is limited in the detection of slow flow and flow in small vessels. The addition of recently developed microbubble-based US contrast agents may improve the detection of low-volume blood flow by increasing the signal-to-noise ratio (12). 1 Andrea Klauser, MD, Michael Schirmer, MD, Leo Pallwein, MD, Manfred Herold, MD, Gernot Helweg, MD, Dieter ZurNedden, MD: University Hospital Innsbruck, Tyrol, Austria; 2Ferdinand Frauscher, MD, Ethan Halpern, MD, MSc: Thomas Jefferson University, Philadelphia, Pennsylvania. Address correspondence and reprint requests to Andrea Klauser, MD, Department of Radiology II, Anichstrasse 35, A-6020 Innsbruck, Austria. E-mail: email@example.com. Submitted for publication June 5, 2001; accepted in revised form October 24, 2001. 647 648 KLAUSER ET AL The goal of this present study was to assess the value of contrast-enhanced CDUS in the evaluation of the extent of intraarticular vascularization of the finger joints in patients with RA. PATIENTS AND METHODS Patients and healthy volunteers. Over a period of 10 months (November 1999 until August 2000), we investigated 198 finger joints in 46 patients with RA (34 women, 12 men; mean age 45.7 years, range 29–71 years). We examined 112 metacarpophalangeal (MCP) joints (77 MCP II and 35 MCP III) and 86 proximal interphalangeal (PIP) joints (54 PIP II and 32 PIP III). The patients were recruited from the rheumatology outpatient clinic of the University Hospital of Innsbruck. All patients had early RA (disease duration ⬍6 months) and fulfilled the American College of Rheumatology (formerly, the American Rheumatism Association) criteria for the diagnosis of RA (13). The patients were examined by 2 rheumatologists (MH and MS). The clinical activity of joint inflammation was determined in accordance with the modified index of synovitis activity, and levels of activity in the joints were classified as active (swollen, warm, and tender), moderately active (swollen and tender), and inactive (only swollen or neither swollen, warm, nor tender) (14). Blood tests were performed to determine serologic activity, including measurement of hemoglobin (Hgb), the erythrocyte sedimentation rate (ESR) (by the Westergren method), C-reactive protein (CRP) (by nephelometry), and rheumatoid factor (RF) (by enzyme-linked immunosorbent assay for IgM-RF). The finger joints of the patients were investigated by conventional radiography using the Larsen score (15). Larsen stages of radiographic joint damage (ranging from 0 to stage V) were determined for each MCP and PIP joint. Furthermore, as controls, we examined 40 MCP and 40 PIP joints (digits II and III of each hand) in 10 healthy volunteers without any history of RA (7 women, 3 men) who were in the same age range as the patients. Color Doppler US. CDUS was performed after the clinical investigation. CDUS was jointly performed and interpreted in consensus by 2 radiologists (AK and FF) who are experienced in musculoskeletal US and who were blinded to the findings of the clinical examination. Longitudinal and transverse US scans of the MCP and PIP joints were obtained from the dorsal view, with the joint in 20° of palmar flexion. We used a gel standoff pad (Sonar Aid; Geistlich, Wolhusen, Switzerland) in all cases. The CDUS examination was done under a constant room temperature of 70°F. Film printouts and videotape records were produced on each case. We used a Sonoline Elegra unit with a VFX 13-5 multi-D linear array transducer, operating at a Doppler frequency of 9 MHz (Siemens Medical Systems—Ultrasound Group, Issaquah, WA). Unenhanced CDUS. CDUS examination was performed to detect intraarticular vascularization, which was defined as color-flow signals in the intraarticular soft tissue or in the pannus. Pannus was defined by its hypoechoic appearance. Vascularization was graded subjectively using a score from 0 to 3 (Table 1). CDUS was performed in both the color Table 1. Criteria for grading intraarticular vascularization with color Doppler ultrasound (CDUS) Grade of vascularization Grade Grade Grade Grade 0 1 2 3 CDUS finding No intraarticular color-flow signals 1–5 intraarticular color-flow signals 6–10 intraarticular color-flow signals 11 or more intraarticular color-flow signals Doppler frequency and the color Doppler amplitude (“power Doppler”) modes. Standardized machine settings (transmit power ⬍500 mW/cm2, a low-pass wall filter, and medium persistence) were used and remained fixed throughout the study. These settings were chosen to maximize sensitivity to low-velocity and low-volume blood flow. The color Doppler gain was optimized by increasing gain until noise appeared and then reducing gain just enough to suppress the noise (usually ⬃60–70% gain). Color Doppler amplitude gain was optimized by turning up the gain until first noise appeared in the background (⬃75–85% gain). We applied the appropriate color velocity scale using the musculoskeletal program of our US unit. The window (color box) was restricted to the vascular area studied. After visualization of color-flow signals, pulsedwave spectral Doppler imaging was performed using the lowest filter setting (125 Hz) and the smallest scale available that would display the Doppler waveforms as large as possible without aliasing. A spectral Doppler tracing was obtained to confirm that the color Doppler signals represented true arterial or venous flow. Contrast-enhanced CDUS. Our study had Institutional Review Board approval and all patients gave their written informed consent prior to the intravenous administration of the US contrast agent Levovist (Schering, Berlin, Germany). This agent contains microbubbles smaller than 8 m, which are strong reflectors of the US beam and therefore improve the strength of the blood-flow signal (Figure 1). The agent was prepared in a standard manner. Fifteen milliliters was administered in a concentration of 300 mg/ml by continuous slowinfusion technique (16) at a rate of 1 ml/minute using a Secura FD perfusor (Braun, Maria Enzersdorf, Austria). This infusion technique was designed to provide uniform, optimal contrast enhancement up to 20 minutes. Subsequently, color Doppler frequency mode, color Doppler amplitude mode, and pulsedwave spectral Doppler imaging were performed with the same technique as in the unenhanced imaging study. The data obtained from unenhanced and contrastenhanced CDUS were compared with the extent of disease activity as assessed on clinical examination. Statistical analysis. The collected data were analyzed using Stata software (version 7.0; Stata, College Station, TX). The degree of vascularization obtained in the finger joints of healthy volunteers was compared with that in patients with RA using the Mann-Whitney 2-sample test. Differences between the degree of vascularization on unenhanced and contrastenhanced CDUS among all subject groups were evaluated by the Wilcoxon matched-pairs signed-rank test (17). In order to compare the grade of intraarticular vascularity among healthy volunteers and the 3 subgroups of patients with RA, 6 sets of comparisons were required for CONTRAST ULTRASOUND FOR DETECTION OF FINGER JOINT VASCULARIZATION IN RA 649 Table 2. Comparison of intraarticular vascularization detected with unenhanced color Doppler ultrasound in the rheumatoid arthritis (RA) subgroups Grade of vascularization Activity in RA joints Inactive (n ⫽ 83) Moderately active (n ⫽ 60) Active (n ⫽ 55) Figure 1. Schematic drawing of the effect of an intravascular microbubble-based ultrasound contrast agent on color Doppler imaging. The microbubbles (large open circles) are stronger reflectors of the ultrasound beam (long arrows) compared with the red blood cells (small, clustered solid circles and short arrows). unenhanced CDUS and 6 sets of comparisons were required for contrast-enhanced CDUS (healthy versus inactive joints; healthy versus moderately active joints; healthy versus active joints; inactive versus moderately active joints; inactive versus active joints; moderately active versus active joints). The adjusted P value for these comparisons was 0.05 divided by 6, or 0.008, based on the Bonferroni method. In order to evaluate the effect of the US contrast agent for finger joint enhancement within the entire RA patient population, as well as for the 3 individual subgroups of patients with RA, 4 different comparisons of unenhanced and contrast-enhanced CDUS were performed (entire population, inactive, moderately active, active). The adjusted P value for these comparisons was 0.05 divided by 4, or 0.0125, by the Bonferroni method (17). RESULTS Clinical findings. On clinical examination of the 198 finger joints among 46 patients with RA, 55 joints were classified as being active, 60 joints as moderately active, and 83 joints as inactive. Serologic tests revealed a mean Hgb level (⫾SD) of 131 gm/liter (⫾25), a mean ESR (⫾SD) of 37 mm/hour (⫾23), and a mean CRP level (⫾SD) of 24 mg/liter (⫾20). The RF was positive in 26 patients (57%). Forty-one patients (89%) had Larsen grades 0 or I, and 5 patients (11%) had a Larsen grade II. Results of CDUS. The US investigation was technically adequate for examination of the MCP and PIP joints in all patients and healthy subjects. Healthy volunteers. Neither unenhanced nor contrast-enhanced CDUS of the healthy joints (40 MCP and 40 PIP joints) demonstrated detectable intraarticular color-flow signals. The mean (⫾SD) examination Grade 0 Grade 1 Grade 2 Grade 3 76 29 23 7 16 6 0 15 16 0 0 10 time for each joint was 3 ⫾ 1.8 minutes for unenhanced CDUS and 4 ⫾ 1.1 minutes for contrast-enhanced CDUS. Patients with RA. Unenhanced CDUS. The mean (⫾SD) examination time per joint with the unenhanced CDUS was 5 ⫾ 1.7 minutes. There was no significant difference between the color Doppler frequency mode and color Doppler amplitude mode in terms of detection of intraarticular vascularization. Unenhanced CDUS detected intraarticular vascularization in 7 of 83 inactive joints (8%), in 31 of 60 moderately active joints (52%), and in 32 of 55 active joints (58%) (Table 2). Contrast-enhanced CDUS. The mean (⫾SD) examination time for the contrast-enhanced CDUS was 5 ⫾ 1.4 minutes. Uniform, subjectively optimal contrast enhancement was achieved for examination times up to 20 minutes using our continuous slow-infusion technique. No substantial clinical side effects from administration of the US contrast agent were observed; 2 patients reported experiencing a sensation of “heat” at the injection site, but this disappeared in ⬍1 minute. Contrast-enhanced CDUS detected intraarticular vascularization in 41 of 83 inactive joints (49%), in 59 of 60 moderately active joints (98%), and in all 55 active joints (Table 3). Compared with unenhanced CDUS, the use of the US contrast agent significantly improved the detection of color-flow signals in all RA subgroups (P ⬍ 0.001) and therefore allowed for improved visualization of the extent of intraarticular vascularization (Figures 2 Table 3. Comparison of intraarticular vascularization detected with contrast-enhanced color Doppler ultrasound in the rheumatoid arthritis (RA) subgroups Grade of vascularization Activity in RA joints Inactive (n ⫽ 83) Moderately active (n ⫽ 60) Active (n ⫽ 55) Grade 0 Grade 1 Grade 2 Grade 3 41 1 0 36 22 0 5 31 17 0 6 38 650 KLAUSER ET AL Based on the detection of increased intraarticular vascularization by contrast-enhanced CDUS and the associated high levels of serologic activity in 11 patients with clinically moderately active RA (24%), the dose of disease-modifying antirheumatic drug (DMARD) and corticosteroids was increased. Figure 2. Longitudinal dorsal ultrasound scan of the proximal interphalangeal joint, showing a small amount of pannus (arrows) in a 35-year-old patient with clinically inactive rheumatoid arthritis. A, Unenhanced color Doppler ultrasound (CDUS) demonstrates no intraarticular color-flow signals. This was defined as grade 0 vascularization. B, Enhanced CDUS demonstrates 2 color-flow signals, corresponding to a grade 1 vascularization. and 3). Comparison of our results in Table 2 (unenhanced) and Table 3 (enhanced) shows that contrastenhanced CDUS is superior for the detection of vascularity, especially at higher levels of disease activity. Contrast-enhanced CDUS showed statistically significant differences in the extent of intraarticular vascularization between the inactive and active joints (P ⬍ 0.001), between the inactive and moderately active joints (P ⬍ 0.001), and between the moderately active and active joints (P ⬍ 0.001), using our subjective score of vascularization (grades 0–3) (Table 4). Figure 3. Longitudinal dorsal ultrasound scan of the proximal interphalangeal joint in a 27-year-old patient with clinically moderately active rheumatoid arthritis. A, Unenhanced scan shows ⬍5 intraarticular color-flow signals (arrows), representing grade 1 vascularization. B, Enhanced color Doppler ultrasound demonstrates significantly increased intraarticular color-flow signals (arrows). The grade of vascularization was classified as 3. CONTRAST ULTRASOUND FOR DETECTION OF FINGER JOINT VASCULARIZATION IN RA Table 4. Unenhanced and contrast-enhanced color Doppler ultrasound (CDUS) findings among the healthy volunteers and the rheumatoid arthritis (RA) subgroups* Healthy volunteers (n ⫽ 40) RA subgroup Inactive (n ⫽ 83) Moderately active (n ⫽ 60) Active (n ⫽ 55) Unenhanced CDUS Contrastenhanced CDUS 0 0 0.08 ⫾ 0.3 0.98 ⫾ 0.9†‡ 1.2 ⫾ 0.8†‡ 0.6 ⫾ 0.5† 1.7 ⫾ 0.6†‡ 2.7 ⫾ 0.4†§ * Values are the mean ⫾ SD grade of vascularization. † P ⬍ 0.001 versus healthy volunteers. ‡ P ⬍ 0.001 versus inactive joints. § P ⬍ 0.001 versus inactive joints and versus moderately active joints. DISCUSSION Early diagnosis of RA and differentiation between inactive and active inflammation in the rheumatoid joint are critical issues for the clinician (18,19). Structural radiographic studies are routinely used for imaging in RA, although conventional radiology has shown limited sensitivity and specificity in the investigation of soft tissues (20). MRI enables examination of soft tissues (i.e., pannus) and bones, but this method has limited availability and is very cost-intensive (20–23). Recent studies of the small finger joints by use of US with high-frequency transducers have been able to demonstrate bone erosions, cartilage damage, as well as local effusion and intraarticular pannus (7,8,24). Functional assessment of the extent of intraarticular vascularization seems to be important in evaluating disease activity. Because hypervascularization correlates with disease activity, CDUS may allow the identification of RA patients with latent, but progressive, arthritis in the small joints. In a previous study, Schmidt et al (10), using unenhanced CDUS in patients with knee joint synovitis, reported that the detection of intraarticular flow signals did not correlate with the number of vessels. However, the existing blood vessels were more intensively perfused during the inflammatory process. We could not confirm these findings. Using contrastenhanced CDUS, we were able to detect more vessels in the joints with active RA. Our findings may differ on the basis of having the advantage of a US contrast agent, which enables the detection of even slow blood flow and blood flow in small vessels. Our observations support the thesis stated by Schmidt et al (10), that contrastenhanced CDUS may increase the detection of even minor perfusion. Our results clearly demonstrate that contrast- 651 enhanced CDUS significantly improves the detection of intraarticular vascularization. Without the use of the US contrast agent, we detected intraarticular vascularization in only 70 (35%) of the 198 inactive, moderately active, and active joints. Contrast-enhanced imaging detected flow signals in 155 (78%) of the 198 inactive, moderately active, and active joints. Because of these CDUS findings and associated increased serologic parameters, the dose of DMARD and corticosteroids was increased in 11 patients with clinically moderately active RA (24%). However, these patients should be evaluated for clinical outcome in a followup study. Therefore, at this time, we do not have sufficient data to recommend contrastenhanced CDUS as a parameter for guiding therapeutic decisions. Our use of the continuous slow-flow infusion technique allowed examination times of up to 20 minutes (using 15 ml contrast), with uniform, subjectively optimal enhancement. Prolonged, stable enhancement with microbubbles contrast permits precise investigation of up to 4 fingers. In comparison, contrast-enhanced CDUS with the bolus technique is limited to ⬃3–4 minutes. Therefore, the infusion technique allows a more cost-effective application of the US contrast agent. In our series, no important clinical side effects from the agent were noted. Only 2 patients complained about a sensation of “heat” at the injection site, which disappeared in ⬍1 minute. Hau et al (11) demonstrated that the extent of intraarticular vascularization differed significantly between joints with inactive RA and those with moderately active RA (P ⬍ 0.02) or those with active RA (P ⬍ 0.05). Their results, using the same US equipment as that used in the present study, are similar to our findings. However, they did not report statistically significant differences between moderately active and active joints. We also failed to demonstrate a significant difference between moderately active and active joints with the use of unenhanced CDUS. Using contrast-enhanced CDUS, we found statistically significant differences between moderately active and active joints (P ⬍ 0.001). We conclude that the administration of the contrast agent results in improved detection of color-flow signals, compared with the unenhanced technique. We evaluated both the frequency and the amplitude (“power”) Doppler mode and did not find a significant difference between both techniques. This is consistent with the findings of Schmidt et al (10), who stated that, surprisingly, there was no higher sensitivity of power Doppler US. However, theoretically, power Doppler should be more sensitive in the detection of blood flow, 652 KLAUSER ET AL but this might also depend on the type of US unit (9). Furthermore, contrast-enhanced studies will allow assessment of time intensity curves that may provide additional information about enhancement kinetics. This may also improve evaluation of disease activity. Furthermore, US contrast agents should have some advantages over MRI contrast imaging, since US contrast agents are less likely to leak into the synovial fluid and will therefore more accurately reflect changes in the intravascular compartment (25). Contrast-enhanced CDUS will improve both the detection and followup of disease activity in patients with RA. In our study, the grading of vascularization was subjective. Newman et al (9) used subjective grading of vascularity on both pre- and posttherapy images and reported good results using this technique. Furthermore, a recent study by Walther et al (26) found a good correlation between subjective grading by the US examiner and the histologic findings. These earlier studies were performed without the use of a US contrast agent. Further studies will be needed to validate subjective quantification of contrast-enhanced color-flow signals in order to further improve the assessment of disease activity. We note several limitations of our study. CDUS findings were interpreted by 2 radiologists in consensus, and therefore we do not have any data about inter- and intraobserver variability. The cost of the US contrast agent was ⬃$60 (United States dollars) per patient. The cost of a high-end US unit, as was used for this study, is ⬃$150,000 (United States dollars). Therefore, the costeffectiveness of contrast-enhanced CDUS should be compared with that of other techniques. Prospective studies with a larger number of patients should be performed, with comparison of radiographs, laboratory, histologic evaluations, and clinical investigations in the course of RA. Based on our preliminary results, we conclude that the use of a microbubble-based US contrast agent significantly improves the detection of blood-flow signal within the PIP and MCP joints. Contrast-enhanced CDUS reveals significant differences in intraarticular vascularization in the finger joints of RA patients in association with the level of disease activity. Therefore, this technique seems to be a helpful adjunct in assessment of disease activity in patients with RA. REFERENCES 1. Zvaifler NJ, Firestein GS. Pannus and pannocytes: alternative models of joint destruction in rheumatoid arthritis. Arthritis Rheum 1994;37:783–9. 2. FitzGerald O, Bresnihan B. Synovial membrane cellularity and vascularity. Ann Rheum Dis 1995;54:511–5. 3. FitzGerald O, Soden M, Yanni G, Robinson R, Bresnihan B. Morphometric analysis of blood vessels in synovial membranes obtained from clinically affected and unaffected knee joints of patients with rheumatoid arthritis. Ann Rheum Dis 1991;50:792–6. 4. Grassi W, De Angelis R, Lamanna G, Cervini C. The clinical features of rheumatoid arthritis. Eur J Radiol 1998 (Suppl);1: 18–24. 5. Sugimoto H, Takeda A, Masuyama J, Furuse M. Early-stage rheumatoid arthritis: diagnostic accuracy of MR imaging. Radiology 1996;198:185–92. 6. Olivieri I, Barozzi L, Favaro L, Pierro A, de Matteis M, Borghi C, et al. Dactylitis in patients with seronegative spondylarthropathy: assessment by ultrasonography and magnetic resonance imaging. Arthritis Rheum 1996;39:1524–8. 7. Grassi W, Tittarelli E, Pirani O, Avaltroni D, Cervini C. Ultrasound examination of metacarpophalangeal joints in rheumatoid arthritis. Scand J Rheumatol 1993;22:243–7. 8. Wakefield RJ, Gibbon WW, Conaghan PG, O’Connor P, McGonagle D, Pease C, et al. The value of sonography in the detection of bone erosions in patients with rheumatoid arthritis. Arthritis Rheum 2000:43:2762–70. 9. Newman JS, Laing TJ, McCarthy CJ, Adler RS. Power Doppler sonography of synovitis: assessment of therapeutic response— preliminary observations. Radiology 1996;198:582–4. 10. Schmidt WA, Völker L, Zacher J, Schläfke M, Ruhnke M, Gromnica-Ihle E. Colour Doppler ultrasonography to detect pannus in knee joint synovitis. Clin Exp Rheumatol 2000;18: 439–44. 11. Hau M, Schultz H, Tony HP, Keberle M, Jahns R, Haerten R, et al. Evaluation of pannus and vascularization of the metacarpophalangeal and proximal interphalangeal joints in rheumatoid arthritis by high-resolution ultrasound (multidimensional linear array). Arthritis Rheum 1999;42:2303–8. 12. Goldberg BB, Liu JB, Forsberg F. Ultrasound contrast agents: a review. Ultrasound Med Biol 1994;20:319–33. 13. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24. 14. Thompson PW, Silman AJ, Kirwan JR, Currey HLF. Articular indices of joint inflammation in rheumatoid arthritis: correlation with the acute-phase response. Arthritis Rheum 1987;30:618–23. 15. Larsen A, Dale K, Eek M. Radiographic evaluation of rheumatoid arthritis and related conditions by standard reference films. Acta Radiol Diagn 1977;18:481–91. 16. Albrecht T, Urbank A, Mahler M, Bauer A, Dore CJ, Blomley MJ, et al. Prolongation and optimization of Doppler enhancement with a microbubble US contrast agent by using continuous infusion: preliminary experience. Radiology 1998;207:339–47. 17. Altman DG. Practical statistics for medical research. 1st ed. London (UK): Chapman and Hall; 1991. 18. Young A, van der Heijde DM. Can we predict aggressive disease? Baillieres Clin Rheumatol 1997;11:27–48. 19. Breedveld FC, Dijkmans BA. Differential therapy in early and late stages of rheumatoid arthritis. Curr Opin Rheumatol 1996;8: 226–9. 20. Ostergaard M, Gideon P, Sorensen K, Hansen M, Stoltenberg M, Hendriksen O, et al. Scoring of synovial membrane hypertrophy and bone erosions by MR imaging in clinically active and inactive rheumatoid arthritis of the wrist. Scand J Rheumatol 1995;24: 212–8. 21. Ostergaard M, Stoltenberg M, Lovgreen-Nielsen P, Volck B, CONTRAST ULTRASOUND FOR DETECTION OF FINGER JOINT VASCULARIZATION IN RA Sonne-Holm S, Lorenzen I. Quantification of synovitis by MRI: correlation between dynamic and static gadolinium-enhanced magnetic resonance imaging and microscopic signs of synovial inflammation. Magn Reson Imaging 1998;16:743–54. 22. Gaffney K, Cookson J, Blades S, Coumbe A, Blake D. Quantitative assessment of the rheumatoid synovial microvascular bed by gadolinium-DTPA enhanced magnetic resonance imaging. Ann Rheum Dis 1998;57:152–7. 23. Waterton JC, Rajanayagam V, Ross BD, Brown D, Whittemore A, Johnstone D. Magnetic resonance methods for measurement of 653 disease progression in rheumatoid arthritis. Magn Reson Imaging 1993;11:1033–8. 24. Schmidt WA. Value of sonography in diagnosis of rheumatoid arthritis. Lancet 2001;357:1056–7. 25. Gibbon WW, Wakefield RJ. Ultrasound in inflammatory disease. Radiol Clin North Am 1999;37:633–51. 26. Walther M, Harms H, Krenn V, Radke S, Faehdrich TP, Gohlke F. Correlation of power Doppler sonography with vascularity of the synovial tissue of the knee joint in patients with osteoarthritis and rheumatoid arthritis. Arthritis Rheum 2001;44:331–8.