Published Online First: 17 May 2006.
doi:10.1136/ard.2005.051235
Annals of the Rheumatic Diseases
2006;65:1590-1595
? 2006 by BMJ Publishing Group Ltd & European League
Against Rheumatism
EXTENDED REPORT |
1 Department of Internal Medicine, Mikkeli Central
Hospital, Mikkeli, Finland
2 Department of Nuclear Medicine,
Mikkeli Central Hospital, Mikkeli, Finland
3 Department of
Pathology, Mikkeli Central Hospital, Mikkeli, Finland
4 Department
of Radiology, Mikkeli Central Hospital, Mikkeli, Finland
Correspondence to:
J Koski
Department of Internal Medicine, Mikkeli Central Hospital,
Porrassalmenkatu 35?37, 50100 Mikkeli, Finland;f.koski@fimnet.fi
Accepted 1 May 2006
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ABSTRACT |
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Methods: 44 synovial sites in small and large joints, bursae and tendon sheaths were depicted with ultrasound. A synovial biopsy was performed on the site depicted and a synovial sample was taken for histopathological evaluation. The performance of three ultrasound devices was tested using flow phantoms.
Results: A positive Doppler signal was detected in 29 of 35 (83%) of the patients with active histological inflammation. In eight additional samples, histological examination showed other pathological synovial findings and a Doppler signal was detected in five of them. No significant correlation was found between the amount of Doppler signal and histological synovitis score (r = 0.239, p = NS). The amount of subsynovial infiltration of polymorphonuclear leucocytes and surface fibrin correlated significantly with the amount of power Doppler signal: r = 0.397 (p<0.01) and 0.328 (p<0.05), respectively. The ultrasound devices differed in showing the smallest detectable flow.
Conclusions: A negative Doppler signal does not exclude the possibility of synovitis. A positive Doppler signal in the synovium is an indicator of an active synovial inflammation in patients. A Doppler signal does not correlate with the extent of the inflammation and it can also be seen in other synovial reactions. It is important that the quality measurements of ultrasound devices are reported, because the results should be evaluated against the quality of the device used.
Abbreviations: PDU, power Doppler ultrasound; PRF, pulse repetition frequency
Grey-scale ultrasound imaging (B mode) is a useful method to find soft tissue lesions in synovial structures such as joints, tendons and bursae, as well as bone erosion.1,2,3,4,5,6,7,8,9,10,11 Circulation is a crucial part of the synovial inflammation process.12,13 Colour Doppler and power Doppler ultrasound (PDU) imaging can detect synovial blood cell movements?that is, perfusion and vessels. PDU is theoretically more sensitive than colour Doppler ultrasound in small-vessel imaging, because PDU provides increased sensitivity to low-volume, low-velocity blood flow at the microvascular level.14 It has been shown that the Doppler signal increases in active synovitis and decreases after a successful intra-articular or systemic treatment showing therapeutic response.15?26 Thus, the activity of a synovial inflammatory state is hoped to be assessed with ultrasound.
The concurrent validity of Doppler ultrasound imaging to show synovitis is not known. There are only a few studies on the correlation between Doppler imaging and the histology of the synovium in patients with rheumatic diseases.27?29 The relatively few joints studied in these papers have been end-stage rheumatic disease of knees and hips. And in two of these three studies only vascularity was reported, not the inflammatory state of the synovial tissue.
Quality-assurance measurements of ultrasound devices have not been reported in scientific clinical articles. Practical work among ultrasound equipments has raised a doubt that some devices might have a more sensitive Doppler mode than others. Thus, the performance of Doppler imaging equipment and probes may play an essential part in evaluating the significance of the results.
Our paper aimed to firstly use PDU to depict small and large joints, bursae and tendon sheaths in patients with rheumatic diseases, and to compare the results with histological samples, and, secondly, to examine the performance of ultrasound devices, especially to show very slow flows.
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MATERIALS AND METHODS |
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Quality-assurance measurements of the power Doppler mode
Quality-assurance measurements were conducted on fast flows (10?200
cm/s) in the Esaote and Toshiba and very slow flows (0.032?3.4 cm/s)
in all three devices. The fast flows were determined using a Model 43
Doppler String Phantom (CIRS, Norfolk, Virginia, USA). As there is no
commercial phantom for slow flow measurements, a phantom was
constructed by UH. We were especially interested in determining the
slowest detectable flow. The ultrasound devices were measured using
"laboratory settings", which make it possible to use the most
sensitive Doppler mode to detect slow flows (eg, minimal pulse
repetition frequency (PRF) value); in the Esaote, we also used
machine settings used in clinical work (clinical settings). The flow
phantom consisted of a block of tissue-mimicking material made of
polyvinyl alcohol cryogel. The block was made at the Department of
Applied Physics, Kuopio University, Finland, and the material was
investigated to ensure that it corresponded with soft tissue (speed
of sound 1540 m/s). A silicone vessel (inner diameter 1 mm) was put
through the 65-mm-thick block at an angle of 35? to the ultrasound
beam (fig 1
). The vessel corresponded to a small blood vessel.
A fluid mimicking blood (BMF, Sidac Engineering, North York, Ontario,
Canada) was pumped through the vessel. The pump used, Perfusor Secura
FT (B Braun, Bethlehem, Pennsylvania, USA), can produce a regular
gradual flow of 1?99 ml/h, which corresponded to a flow of 0.32?34
mm/s in the vessel used. The real mean flow was checked by following
the air-bubble movement in the vessel for a distance of 40 cm. The
real velocity of the flow in the vessel and the flows measured by the
devices were checked three times at every pump speed. The flow
measurements inside the block were conducted to the depth of 25?35
mm.
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shows the clinical characteristics, laboratory
findings, drugs and x ray status according to Larsen?s method30
of the patients. There were no changes in the drugs or
intra-articular injections during the 3 months preceding the
intervention. The diagnoses established were based on the criteria of
the American College of Rheumatology31 and the European
Spondylarthropathy Study Group.32 Consecutively, all the
patients of the clinic scheduled for a synovial biopsy volunteered
for the study. The indication for a synovial biopsy was clinical in
each case.33
The ultrasound examination was performed at room
temperature
(22?C) and the sonographer used minimal probe pressure after
applying gel on the skin. The scanning of the anatomical sites
was carried out with standard scans2 to locate effusion and
synovial hypertrophy, and to estimate the power Doppler signal. The
effusion was defined as hypoechoic or anechoic fully compressible
material, the synovial hypertrophy as echogenic or hypoechoic
slightly compressible or non-compressible material, fixed intra-articular
tissue and the Doppler signal as a stagnant (or tube-like) pulsating
colour spot found inside the synovial structure. The colour box was
adjusted to cover the region of interest. The settings of the Esaote
were PRF 500 MHz, colour emission frequency 8.3 MHz (LA424), 7.1 MHz
(LA523), low wall filter and movement artefact suppression parameter
3 (range 0 (absent) to 4 (high)). The colour priority, dynamic range
and persistence were set high. The colour gain was increased until
background noise appeared and then reduced until the noise was
suppressed. Flow was also shown on two planes. The image with maximum
colour activity
was chosen for analysis. The grey scale as well as PDU findings
were reported subjectively and graded on a semiquantitative
scale from 0 to 3: 0 for no effusion, synovial proliferation or
colour signal; 1 for mild effusion, proliferation or colour signal; 2
for moderate effusion, proliferation or colour signal; and 3 for a
substantial increase of effusion, proliferation or colour signal.
A percutaneous synovial biopsy of the scanned synovial structure was performed under ultrasound guidance immediately after the ultrasound imaging. In 10 patients, there was a maximum of a 24-h delay between the two procedures. The patients? drugs were kept constant during the delay. An exact description of the biopsy method and the handling of the samples have been published earlier.33
The synovial samples were all examined once under blinded
conditions
by the histopathologist MH. Only sections with an intact synovial
lining layer were included. Seven histological parameters of
the specimen were determined separately: multiplication of synovial
lining, villous hypertrophy of the synovial surface, surface
fibrin deposition, subsynovial infiltration of polymorphonuclear
leucocytes, subsynovial infiltration of mononuclear leucocytes,
proliferation of blood vessels and fibrosis. Each parameter was
graded on a semiquantitative scale from 0 to 3 according to the
amount of the character: 0 points for no existence; 1 point for mild
evidence; 2 points for moderate evidence; and 3 points for a
substantial increase in the particular character. The points were
counted for an overall histopathological score (points 0?21) in each
sample. A score of 
2 points in an individual sample was regarded as
pathological. The histological sample was regarded as actively
inflammatory (active synovitis) if leucocytes were present and as a
pathological synovial reaction if any of the other characters were
present without leucocytes.
The study was approved by the local ethical committee and each patient gave informed consent.
Statistical analysis
Statistical analyses
were carried out using SPSS V.13 software. Spearman?s r correlation
analyses between variables were tested for two-tailed probability
values. Values of p<0.05 were considered significant.
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RESULTS |
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). In the LA523 (Esaote), the value was 1.6 mm/s and
that in the UST 5710 (Aloka) was 6.7 mm/s. The slowest detectable
flows on clinical settings of the Esaote were 2.2 and 2.5 mm/s for
the probes LA424 and LA523, respectively. The most sensitive Doppler
mode could be achieved in probe LA424, with a colour emission
frequency of 8.3 MHz, PRF of 250 Hz, low wall filter, scan
correlation parameter 1 and movement artefact suppression parameter
1. The corresponding settings for the LA523 were colour emission
frequency 7.1 MHz, PRF of 250 Hz, low wall filter, scan correlation
parameter 1 and movement artefact suppression parameter 1.
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). There were two cases where only fibrosis could be
found histologically, but PDU showed a strong intra-articular signal
(ie, proliferative stage of the fibrosis).
No significant correlation was found between the amount of
the
power Doppler signal in the synovium and the overall histopathological
score (r = 0.239, p = NS; fig 3). The amounts of subsynovial infiltration of
polymorphonuclear leucocytes and surface fibrin were the only
histological parameters that correlated significantly with the amount
of power Doppler signal: r = 0.397 (p<0.01) and 0.328 (p<0.05),
respectively (table 3). No divergence was observed between the various
synovial sites examined.
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DISCUSSION |
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Perfusion in the synovium can be evaluated by using a subjective semiquantitative scale of colour signals, a quantitative measurement of colour pixels or by analysing the Doppler curves. We chose to assess the power Doppler signal subjectively on a scale of 0?3. This method is easy to use in daily work and it has been shown to correlate with digital image analysis.28 The phantom part of the paper showed that a visual observation of the flow (ie, assessing the colours) seemed to be more sensitive than measuring the flow from the Doppler curve (pulsed-wave Doppler).
Histopathology and correlation with ultrasound scanning
We did not find any significant correlation between the amount of
Doppler signal and the histopathological score of synovitis. This is
at odds with the prevailing conception but this is also the only
study of its kind. The histological analysis by Schmidt et al27
was different. The authors found a good agreement between the
presence of colour signals and histologically verified pannus tissue.
The finding that the amount of Doppler signal and the histopathological state do not correlate significantly makes the use of the semiquantitative scale of Doppler signal questionable in the grading of synovitis in clinical work as well as in scientific papers. Instead, a dichotomous scale (yes/no) could be better, and here only a positive Doppler signal seems to be significant in terms of reliability in evaluating synovitis. The finding also casts a shadow on using PDU in treatment monitoring. A diminishing of colour in PDU found in the follow-up of the joint treated is inevitably an indicator of a good response, but, according to this study, a negative Doppler signal does not exclude inflammation.
The heterogeneity of the diseases investigated was a problem for this study. Owing to the small number of patients in the subgroups, a detailed histological analysis versus diagnoses or markers for disease activity was not carried out.
It is not possible to calculate the concurrent validity of PDU in this material because of a lack of healthy specimens. However, the sensitivity of PDU in showing synovial inflammation or other pathological synovial reactions in this material seemed to be quite good. It is also important to realise that it is difficult to give generalised validity figures about Doppler imaging because the results are inevitably device dependent. Using a device with a more sensitive Doppler mode could give different results, something that remains to be proved.
Conflicting reports of the Doppler signal in a normal joint are available. Most researchers report normal joints to be negative, but colour Doppler activity in normal hand joints has been reported in 11?18%36,37 of cases. The distinguishing feature between normal and pathological joints is that pathological grey-scale changes are missing in a normal joint.
We did not find a positive correlation between the amount of Doppler signal and vessels detected histologically. This was in accordance with Schmidt?s study.27 However, Walther et al28,29 found a close correlation between the power Doppler flow and the amount of vessels in two studies. Biopsy methods (percutaneous v open) do not explain the difference, as Schmidt and Walther both used open biopsies. The staining method in Walther?s paper was different: haematoxylin and eosin and factor VIIII staining for the detection of vessels. The preparation and staining of the sample was not described in Schmidt?s paper.
Using histological examination as a gold standard is problematic. Firstly, there is no accepted uniform scoring system of inflammation in the evaluation of synovitis. We used a system of seven parameters, which included typical phenomena in the inflammation process found using haematoxylin and eosin staining. Secondly, what is actually an active (significant) synovitis assessed in histopathology using haemotoxylin and eosin staining? We defined active synovitis as leucocytes found in the synovium. However, there were no leucocytes in 8 of 43 (18.6%) samples with pathological findings (in five of them the Doppler signal was positive), but other mixed reactions could be found. Fibrosis inevitably represents the reparative state of inflammation, but other synovial reactions may signal an early or a late phase of the inflammation process. Thus, the PDU could not distinguish between active synovitis and other types of pathological synovial reactions. Thirdly, only relatively little information is available on the histology of the synovium in a normal living person. One study38 found several phenomena usually related to the inflammatory state in a normal synovium. Therefore, the line between normal and pathological synovia remains obscure. A histological assessment is nevertheless widely regarded as the gold standard to which other methods of assessment should be related.
In conclusion, this paper shows that a negative power Doppler signal in the synovium does not exclude the possibility of synovitis, but that a positive Doppler signal is a significant marker for synovitis in patients. Even a minor colour signal detected in the synovium is important in terms of histopathology, but the amount of colour in PDU does not correlate significantly with the severity of histopathological synovitis. A PDU signal can be seen in various synovial reactions. In Doppler imaging, the significance of the results should be evaluated against the performance of the equipment used.
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FOOTNOTES |
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Funding: This study was supported by an EVO grant.
Competing interests: None.
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REFERENCES |
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