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Original Research |
1 Department of Diagnostic Radiology, Medical University of Vienna, Waehringer
Guertel 18-20, A-1090 Vienna, Austria.
2 Department of Rheumatology, Internal Medicine III, Medical University of
Vienna, Vienna, Austria.
Received December 16, 2005;
accepted after revision March 15, 2006.
Address correspondence to C. Schueller-Weidekamm
(claudia.schueller-weidekamm{at}meduniwien.ac.at).
Abstract
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MATERIALS AND METHODS. Before and after 7 days of mid- to high-dose steroid therapy, blood tests and clinical and sonographic examinations were assessed in 14 patients. Two hundred eighty finger joints (metacarpophalangeal [MCP] I-V, interphalangeal [IP], and proximal interphalangeal [PIP] II-V) were investigated on power Doppler sonography to determine, in each patient, the finger joint with the strongest hypervascularization and to score the synovial vascularization. Further dynamic examination of the selected joint was performed on PIHI after IV administration of a second-generation sonographic contrast medium. Vascularization was quantified by calculating the area under the time-intensity curves. The changes in signal intensities before and after therapy were correlated with clinical examinations (disease activity score [DAS]).
RESULTS. The score of the joint with the strongest hypervascularization assessed by power Doppler sonography decreased significantly from 1.7 to 1.3 (p < 0.01); however, in six patients, no change was assessed after steroid therapy. In all patients, a significant reduction in PIHI signals was observed after therapy (p < 0.05). The baseline and follow-up median values of the area under the time-intensity curves were 8.56 ± 1.28 and 7.65 ± 0.66, respectively. The median values of the DAS decreased significantly from 4.90 ± 0.86 to 3.6 ± 1.0 (p < 0.01) 7 days after the steroid therapy.
CONCLUSION. PIHI and power Doppler sonography enable the detection of synovial perfusion alterations after steroid therapy and, therefore, may be useful tools for the evaluation of active inflammation in RA and for the assessment of therapeutic response. However, minor changes of synovial vascularization can be better detected on PIHI than on power Doppler sonography.
Keywords: joint • musculoskeletal system • pulse-inversion harmonic imaging • rheumatoid arthritis • sonography • synovitis
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Using B-mode and Doppler sonography, detailed anatomy and the blood flow patterns of the vessels in the finger joints can be displayed. To detect and quantify even minute changes in blood flow, the application of contrast material is useful because it improves the signal-to-noise ratio [5-8].
With the advent of new microbubble contrast materials in sonography, an imaging technique has been rapidly developed to provide a better depiction of hypervascularization [9]. Pulse-inversion harmonic imaging (PIHI) is a new sonographic technique that consists of a sequence of two reciprocal ultrasound waves transmitted into the tissue to subtract the signal from a linear medium such as tissue. Microbubble contrast material is a nonlinear medium because of the asymmetric expansion and contraction of gas bubbles, and thus it remains in the tissue for echo signal detection [10, 11]. PIHI exploits the properties of microbubble contrast materials, which are based on the generation of harmonics from nonlinear oscillation of bubbles and on stimulated acoustic emission effects from the destruction of bubble walls [12].
The purpose of this study was to assess the changes in vascularization in the finger joints of patients with RA before and after mid- to high-dose steroid therapy on contrast-enhanced PIHI in comparison with power Doppler sonography.
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Before and after 7 days of therapy, blood tests and clinical and sonographic examinations were assessed. Blood tests included measurement of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and rheumatoid factor (RF). Patients were examined clinically by two rheumatologists and joint inflammation activity, including swollen or tender joints or both, was assessed by the DAS-28 score. The difference between the before and after treatment scores represents the range of inflammation that would be amenable to steroid therapy.
Sonography Investigation
Investigators were blinded to the clinical data. Two radiologists
experienced in the use of this sonography technique for at least 5 years,
examined 140 metacarpophalangeal (MCP) joints, 112 proximal interphalangeal
(PIP) joints, and 28 interphalangeal (IP) joints on power Doppler sonography.
Power Doppler examinations of each patient were performed in consensus by two
radiologists within one session. Contrast-enhanced PIHI was performed by one
radiologist using a single-bolus injection of contrast material. A sonography
scanner (HDI 5000, Philips Medical Systems) with a 5-12-MHz phased-array
transducer for Doppler imaging and equipped with dedicated Doppler software
was used. Each examination was performed in combination with an acoustic
standoff pad (Sonar-Aid, Geistlich Pharma) for better focusing, avoiding
motion artifacts, and improving surface contact. Power Doppler was performed
with a standardized technique in transversal and longitudinal cuts dorsally
for depiction and scoring of the most hypervascularized finger joint in each
patient
[19-23]
(Fig. 1A). The patient was
seated at the scanning table opposite the investigating physician with the
hands placed flat on the table surface. According to previous studies, power
Doppler findings regarding vascularization were scored on real-time
prospective imaging using a 4-point range (0-3). Grade 1 was defined as normal
(no additional flow except in the dorsal MCP vessels), grade 2 was defined as
slightly increased vascularization, grade 3 was defined as moderately
increased vascularization, and grade 3 as strongly increased vascularization
[19,
20]. Power Doppler
standardization was based on two criteria. First, the small vessels of the
hands (dorsal MCP vessels) had to be visible. Second, the color gain setting
had to be selected on a level slightly lower than noise. The color box was
restricted to the vascular area studied. A pulse repetition frequency of
750-1,000 KHz was used.
Those joints indicating the strongest vascularization in each patient were further examined on contrast-enhanced PIHI in transversal cuts dorsally with a 4-7-MHz phased-array transducer using a low mechanical index (< 0.1). For each case, film printouts and videotape records were produced.
SonoVue (sulfur hexafluoride, Bracco) was used as the sonographic microbubble contrast material (mean bubble size, 2.5 µm; resistant to low and medium acoustic power). SonoVue does not diffuse into the extravascular compartment and is removed from the blood circulation by the pulmonary route, with 80-90% of the injected dose eliminated by 11 minutes after administration [24]. SonoVue improves the visualization of the small vessels by reflecting sound waves and therefore improves the signal-to-noise ratio.
For each investigated joint, 2.4 mL of contrast material was administered at a rate of approximately 1 mL/s as a bolus injection followed by a 5-mL saline solution flush via a 20-gauge IV catheter placed in an antecubital vein. Before contrast material injection, three baseline images were recorded on videotape. The PIHI examination was triggered to an ECG to provide a longer scanning time (up to 3 minutes). Images were recorded at a rate of one frame per heart cycle. Signal intensities were documented by an integrated magnetic optical drive on the sonography scanner.
After mid- to high-dose steroid therapy, the power Doppler examination was repeated for those joints that showed the strongest vascularization in the pretreatment examination. In the standardized technique for power Doppler sonography, the follow-up examination was performed in the same plane as the initial examination with respect to anatomic landmarks. The PIHI examination was repeated for the same joint in transversal cuts dorsally. Review of the initial images was helpful for minimizing variability related to transducer positioning.
In this study, synovial thickness before and after therapy was not compared, and erosions detected on sonography were not assessed.
Data Analysis
Sonograms were transferred to a PC workstation. A rectangular region of
interest (ROI) (mean size, 87.68 mm2; size range, 84.63-102.13
mm2) was set to surround the synovial tissue for further
quantification of vascularization. Analysis was performed with dedicated
software (Q-LAB, Philips Medical Systems) and transferred into an Excel
database (Microsoft). The area under the time-intensity curve (AUC) was
measured in each examination, and the results of the baseline and follow-up
investigations were compared.
Statistical analysis was performed using PC spreadsheet software (SPSS, version 11.5). The AUC for each patient indicates contrast material accumulation within the ROI. Differences in AUC before and after therapy were compared using the Wilcoxon's signed rank test. A p value of < 0.05 indicated a significant difference in sonographic intensity. Power Doppler scores before and after therapy were compared using the Wilcoxon's signed rank test. Patient DAS-28 values before and after therapy were tested for normal distribution, and differences between before and after therapy values were determined using the paired Student's t test. All data are expressed as mean ± SEM.
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Clinical Findings
On clinical examination, joint swelling was documented in 46 of 140 MCP
joints, in 36 of 112 PIP joints, and in 4 of 28 IP joints. At follow-up, 34 of
140 MCP joints, 30 of 112 PIP joints, and 2 of 28 IP joints were still
swollen. Tenderness was documented in 34 of 140 MCP joints, 32 of 112 PIP
joints, and 12 of 28 IP joints before therapy and 20 of 140 MCP joints, 16 of
112 PIP joints, and 2 of 28 IP joints after therapy. On enrollment, 30.7% of
the finger joints were classified as swollen and 27.6% as tender, whereas
23.6% of the joints were classified as swollen and 13.6% as tender after 7
days of mid- to high-dose steroid administration.
CRP levels and the ESR were significantly reduced (Table 1). The DAS-28 score before treatment was 4.90 ± 0.86 (range, 3.60-6.39) and was reduced to 3.6 ± 1.0 (range, 2.45-5.39) after treatment (p < 0.01). Twenty-nine percent of the patients had a positive RF—before therapy, 443 IU/mL (range, 71-814); after therapy, 244 IU/mL (range, 68-420).
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Sonographic Findings
The distribution of the joints with the strongest hypervascularization that
were selected for further investigation with contrast material included 28.5%
in the MCP II, 21.4% in the PIP III, and 14.3% in the MCP III. In 57% of the
patients, a reduction of synovial hypervascularization was detected on power
Doppler sonography (95% CI, 27.5-86.7%) (p <0.01) (Fig.
1A,
1B). In six patients, no change
of the score was assessed, whereas all other patients showed a reduction in
the score from 3 to 2 (n = 4) and from 2 to 1 (n = 4)
(Table 2). None of the patients
showed an upgrade in the score.
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On PIHI, at the pretreatment baseline investigations, significantly higher levels of signal intensity were measured than on the follow-up investigations after 7 days of steroid therapy. The median values of the AUC were 8.56 ± 1.28 and 7.65 ± 0.66 in patients before steroid therapy and 7 days after steroid therapy, respectively (Fig. 2). The comparison among the median values of the AUC showed a statistically significant reduction in blood flow in intraarticular vascularization after therapy (p < 0.037). All patients showed a reduction of synovial hypervascularization on PIHI, even if there was no change of vascularization detected on power Doppler.
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This study provides radiologic confirmation of inflammatory disease activity, which is useful in monitoring therapeutic effectiveness. The differentiation between joint effusion and synovitis is still a challenge for sonography because both can be imaged as hypoechoic structures in the B-mode application. The use of color and power Doppler imaging has been proven to be a suitable diagnostic tool for the assessment of intraarticular vascularization, indicating active synovitis. Several studies have shown that hypervascularization of the synovial tissue correlates with disease activity in RA [8, 9, 19]. Those studies investigated the diagnostic value of power Doppler sonography or contrast-enhanced power Doppler sonography in patients with early RA. The purpose of those studies was to improve the diagnosis of early RA for therapeutic reasons using new sonographic techniques.
Our study investigated the changes of hypervascularization after steroid therapy on two different sonography techniques: power Doppler sonography and contrast-enhanced PIHI. Both techniques showed a significant decrease of synovial vascularization after therapy. However, on power Doppler sonography, decreases from moderate to slight vascularization or strong to moderate vascularization were found in only 57% of the patients. In six patients, no reduction in the semiquantitative scoring system could be detected after steroid therapy.
With PIHI, all patients showed a decrease of synovial vascularization even though in some patients these changes were only minor. In accordance with other studies that showed that contrast-enhanced sonography techniques improve the detection of synovial hypervascularization [25, 26], we found a better detection of minor changes of synovial vascularization on contrast-enhanced PIHI. However, we believe that both sonography techniques enable the differentiation between synovial perfusion and joint effusion because each patient showed minor to strong synovial vascularization on power Doppler sonography and PIHI.
To our knowledge, this is the first report on the use of a new harmonic imaging sonography technique (PIHI) with a sonographic contrast material for the quantification of intraarticular vascularization. A recent study has shown that contrast-enhanced PIHI is suitable for the detection of slow blood flow in small brain vessels [27]. The advantage of PIHI is the initial transmission of two reciprocal pulses to subtract fundamental signals of the tissue. This allows the use of broader transmit and receive bandwidths for improved resolution and increased sensitivity to contrast [28]. A low mechanical index was used to prolong the lifetime of the contrast agent and to increase the acoustic signal of the microbubbles that expand and contract [29].
A bolus technique for contrast material administration was used to determine the median signal intensity of the intravascular microbubbles and to evaluate the time-intensity curve for 3 minutes. SonoVue is an intravascular contrast material that does not cause tissue perfusion (respiratory elimination). Therefore, we conclude that the differences before and after therapy are due to more intensively perfused small vessels, on the one hand, and an increased number of small vessels caused by the inflammatory process on the other hand [1].
The main limitation of this study is the comparatively small number of patients. However, the data were significant and strongly suggest that PIHI is a useful tool for imaging alterations in synovial perfusion. Second, only one affected joint could be investigated with a single contrast material bolus application. For this reason, before contrast material application, we performed power Doppler sonography to select the finger joint that showed the strongest hypervascularization. The use of clinical examination as a gold standard is not ideal because there may be false-positive or false-negative results. On a related note, a test can only perform as well as its gold standard does, so at best, this new sonography technique can only match a clinical examination (which is not ideal). This shows the need for a better gold standard. The limited capacity for recording the dynamic sonography examination with PIHI on videotape was overcome by the fact that the PIHI examination was triggered to ECG and only one image was recorded per heart action. Different scoring systems for sonographic assessment of joint inflammation were used for the two techniques—power Doppler sonography, semiquantitative 4-point scale; contrast-enhanced PIHI, quantitative perfusion intensity (AUC). Therefore, a statistical test for comparison of the two techniques could not be used.
In conclusion, contrast-enhanced sonography with a PIHI technique and power Doppler sonography enable the detection of synovial perfusion alterations after mid- to high-dose steroid therapy by quantification of synovial perfusion in finger joints. Minor changes of synovial vascularization can be better detected on PIHI than on power Doppler sonography. PIHI may be an additional tool for the evaluation of active inflammation components in RA and for the assessment of therapeutic response.
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