Power Doppler ultrasound of rheumatoid synovitis: quantification of therapeutic response

Transcription

1 The British Journal of Radiology, 76 (2003), DOI: /bjr/ E 2003 The British Institute of Radiology Power Doppler ultrasound of rheumatoid synovitis: quantification of therapeutic response J TEH, K STEVES, L WILLIAMSO, J LEUG and EGMCALLY Department of Radiology, uffield Orthopaedic Centre, Windmill Road, Headington, Oxford OX3 7LD, UK Abstract. The aim of this study is to quantify power Doppler assessment of therapeutic response in rheumatoid synovitis. 13 patients (6 male, 7 female) with rheumatoid arthritis, who had an acute exacerbation of small joint synovitis in the hands, were examined with quantitative power Doppler, before and after intravenous corticosteroid treatment. All patients were examined by a single radiologist, using an ATL HDI 5000 ultrasound machine (ATL, Boswell). The images were analysed using a specially developed software package (HDI Lab), which quantifies power Doppler signal. All patients improved clinically following treatment, which was reflected in functional disability scores, and in the C-reactive protein levels and erythrocyte sedimentation rate. In all cases, there was a significant decrease in synovial vascularity as measured by the mean amplitude of signal on quantitative power Doppler. Quantitative power Doppler may allow objective assessment of treatment in small joint synovitis. In patients with rheumatoid arthritis, assessment of disease activity and therapeutic response has predominantly relied on clinical assessment and serum markers of inflammation. Plain film radiography, although good for established erosions, gives little information on synovial inflammation and early erosions [1]. Several studies have shown that gadolinium enhanced MRI may demonstrate synovitis, but this is difficult to quantify [2, 3]. Ultrasound has been shown to effectively demonstrate effusions, synovial hypertrophy and erosions [4]. Colour Doppler, although sensitive to high-velocity flow, is less effective in depicting low velocity microvascular flow, and is therefore poor at assessing synovial blood flow [5]. However, power Doppler (PD), which is essentially angle-independent and free from aliasing, has been shown to reliably assess synovial blood flow [6 8]. Previous studies have suggested that therapeutic response may be assessed by PD, but the investigators relied purely on subjective visual scale readings [7, 9]. Recent software developments allow objective quantification of PD signal, by counting pixels in a specific area of interest, thus allowing more reliable assessment of vascular flow pre and post treatment. The aim of this study was to use quantitative power Doppler (QPD) to assess changes in synovial blood flow and thus therapeutic response in rheumatoid arthritis. Methods and materials 13 consecutive patients with an acute exacerbation of rheumatoid arthritis were enrolled in this study over a period of 7 months. All patients fulfilled the 1987 American College of Rheumatology diagnostic criteria for rheumatoid arthritis [10] and had established disease, which had been present for 1 year to 22 years. Each had complained of worsening symptoms specifically related to the hands over the preceding week. In each case a clinical decision had been made prior to entry into the study that the patient would undergo intravenous corticosteroid therapy. Received 28 October 2002 and in final form 30 June 2003, accepted 29 August The 6 male and 7 female patients aged from 45 years to 80 years (mean 58.5 years), were examined clinically and with QPD, before and after 1000 mg intravenous methylprednisolone. Functional disability was assessed by the Stanford Health Assessment Questionnaire (HAQ) [11] and Overall Status in Rheumatoid Arthritis (OSRA) scores [12], which are both validated for disease activity in rheumatoid arthritis. Serological activity was assessed by the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Before and after scans used an identical protocol, the latter undertaken between 42 h and 70 h (mean 52 h) following treatment. This second ultrasound was performed when an improvement in symptoms was reported by the patient and reflected in a HAQ improvement of at least five points [11]. All patients enrolled in the study had an improvement in symptoms following treatment. Ultrasound was performed by a single operator, using an ATL HDI 5000 ultrasound scanner (ATL, Boswell) and a 5 12 MHz variable frequency probe. The probe was placed sagittally, either across the index or middle finger metacarpo-phalangeal joint, according to which was the more symptomatic. Scanning initially used conventional greyscale, to detect joint effusions, erosions and synovial thickening. This was followed by PD (Figures 1 and 2). PD settings were standardized for each patient and optimized for detection of synovial blood flow by adjusting colour gain, pulse repetition and flow optimization parameters. The colour gain threshold was set at the level just above which no signal was seen within bone, as the bone surface is a strong specular reflector and spurious Doppler signal may occur at the cortical-soft tissue interface [13, 14]. This is different from other anatomical areas, e.g. kidney, where the gain is usually set to just above the noise floor level. To maximize demonstration of small synovial blood vessels, the flow optimization parameters were set to low for all patients, which in turn automatically determined the pulse repetition frequency. The sample box size was initially set to include the whole joint to obtain an overview, and then reduced to include the superficial portion of the joint and the adjacent synovium. 875

2 J Teh, K Stevens, L Williamson et al Figure 1. Pre-treatment power Doppler ultrasound scan of a middle finger metacarpo-phalangeal joint showing synovial hypertrophy and increased vascularity. Figure 3. The power Doppler spectrum, representing power Doppler quantity over time. Pre- and post-treatment spectra are compared for the same patient. Results Before treatment, all patients showed synovial hypertrophy and hyperaemia on ultrasound. All had good early clinical response to intravenous corticosteroids, which was reflected in HAQ and OSRA scores, and serum inflammatory markers (ESR and CRP) (Table 1). Statistical analysis was performed using non-parametric tests and the SPSS 10 program. Figure 2. Post-treatment power Doppler ultrasound scan (of the same patient as Figure 1), demonstrating a significant decrease in synovial hypertrophy and vascularity. The examination parameters were recorded for each patient and care was taken to ensure these remained the same on the subsequent examination. To make certain that the probe was repositioned precisely, the sonographer had images from the previous study displayed on a laptop computer, allowing a comparative image to be obtained. To ensure that vessels were not compressed inadvertently, a small jelly stand-off was used for each examination. Short cine loops (approximately 5 s) of dynamic PD scans were obtained for each observation to allow for several cardiac cycles, whilst being short enough a period for the patient and sonographer to remain absolutely still. Data were transferred onto a PC workstation and analysed using a specially developed software package, HDI lab. This program allows the amount of PD signal within the area of interest to be quantified by a process of pixel counting, producing a trace over time which was labelled the power Doppler spectrum (PDS) (Figure 3). Each joint was scanned three times and the mean power Doppler quantity calculated to minimize intraobserver error. The mean power Doppler quantity was obtained over three complete cardiac cycles to avoid error from different portions of the spectrum being included. The Wilcoxon Rank Sum test showed highly significant decreases (p,0.001) in mean QPD following treatment (Figure 4). There were significant decreases in the functional disability scores (HAQ and OSRA) and inflammatory markers (ESR and CRP) following treatment (Wilcoxon Rank Sum test p,0.001) (Table 1). There was significant correlation (p50.012, Spearman correlation) between decrease in HAQ scores and QPD (Figure 5). There was no significant correlation between change in ESR and CRP and change in QPD however. Discussion Power Doppler ultrasound has been shown to reliably depict soft tissue hyperaemia associated with inflammation of tendons and bursae [6]. Several studies have shown that synovial vascularity may reflect disease activity in inflammatory or infective arthritis [7, 15]. The formation of new blood vessels angiogenesis is now established as the main factor in the formation and maintenance of pannus in rheumatoid arthritis [16, 17]. Synovial vascularity demonstrated on PD has been shown to correlate well with histological findings [16]. Intravenous corticosteroid treatment has been widely adopted to treat acute exacerbations of rheumatoid arthritis [18, 19]. It is recognised that the onset of action is rapid, with measurable changes in symptoms and lymphocytes, immune complexes, and CRP levels in synovial fluid and blood at 4 h and 24 h post-infusion [20, 21]. ewman et al [7] observed that PD might show a decrease in soft tissue hyperaemia after corticosteroids in patients with arthritis. Similarly, Stone et al [9], showed 876

3 Power Doppler ultrasound of rheumatoid synovitis Table 1. The change in mean power Doppler quantity, functional disability scores and laboratory tests after intravenous corticosteroids, expressed as percentage decrease Patient number Sex Age (years) Percentage (%) decrease after steroid therapy Doppler quantity HAQ ORSA CRP ESR 1 M F M M M M M F F F F F F Wilcoxon Rank Sum Test p,0.001 p,0.001 p,0.001 p,0.001 p,0.001 HAQ, Stanford Health Assessment Questionnaire; ORSA, Overall Status in Rheumatoid Arthritis; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate. that PD may be a useful adjunct to disease assessment and response to treatment in rheumatoid arthritis. These investigators, however, relied on subjective visual observations for grading synovial vascularity. Advances in technology now allow the objective quantification of PD signal by counting the number of colour pixels in a specific region of interest [22, 23]. In the present study, changes in QPD were highly correlated with changes in HAQ, suggesting that this technique may have a role in objectively assessing therapeutic response in rheumatoid arthritis. It is important to emphasise that a decrease in PD signal quantity implies a decrease in synovial flow, as it is not known if this is due to fewer vessels or less flow in the same number of vessels. Furthermore, previous studies [6 9] have evaluated single static images in grading vascularity, whereas the present study measures the PD signal over several seconds, allowing several cardiac cycles, giving a PDS. The PDS was assumed to reflect the predominant vessel type of that particular area of synovium. In some patients there was a phasic pattern, consistent with mainly arteriolar flow. In others, the flow was less variable, consistent with predominantly capillary or venous flow. If only static images were utilized, as in other studies [6 9], it may have been difficult to detect small differences in synovial blood flow, particularly if the images were captured in opposite phases of the spectrum. The results show a significant decrease in the QPD following treatment. These decreases correlate with the changes in HAQ scores (p,0.012), but not with other indicators (OSRA score, ESR and CRP) of therapeutic response. Overall changes in laboratory tests were not found to correlate with the changes in functional disability scores. Previous studies have also shown early improvement in clinical and laboratory tests following methylprednisolone treatment without demonstrating good correlation between them [21, 24]. There are several possible reasons for this lack of correlation. Firstly, changes in clinical and biochemical measurements may lag behind changes in synovial vascularity. Furthermore, Figure 4. High low graph demonstrating the mean power Doppler quantity pre- and post-treatment for each patient. Figure 5. Graph demonstrating the close correlation (p50.012) between the percentage change in mean Doppler quantity with the percentage change in Stanford Health Assessment Questionnaire (HAQ) score. 877

4 J Teh, K Stevens, L Williamson et al laboratory tests assess systemic disease rather than local disease activity. Also, only a relatively small number of patients was studied. MRI may also have an important role in assessing activity in synovitis [2, 3]. There are advantages over ultrasound, in that it can cover a wider area and thus several joints in the hands in a single examination. Also MRI does not appear to suffer from problems with repositioning. However, assessment of disease activity using MRI relies on measurement of synovial volume and rates of synovial enhancement [25], rather than direct assessment of blood flow. There is a close relationship between the presence of vascular flow seen on PD and the rate of early synovial enhancement on dynamic gadolinium enhanced MRI [16], but it remains to be shown if very early changes following therapy can be detected on MRI. Although therapeutic response may be judged on clinical grounds alone, QPD monitoring of response may allow a more accurate assessment of disease activity. In early rheumatoid arthritis, there is an association between synovial vascularity as demonstrated on PD and joint erosions [16], implicating vascular pannus in the erosive phase of the disease. Quantitative power Doppler monitoring may prove particularly valuable in patients in whom local therapeutic effects need to be measured, as laboratory tests of systemic disease activity, such as the CRP and ESR, are not specific. In addition, serial QPD examinations may have a role in assessing progression of synovitis in early rheumatoid disease, and thus help determine if and when disease modifying drugs are to be used. Furthermore, several potential therapies for rheumatoid arthritis are emerging that are aimed at inhibiting synovial angiogenesis [26, 27] and QPD could be useful in assessment of their activity. Limitations are that serial QPD examinations are timeconsuming, and may be difficult in larger joints, as exact probe repositioning may be more difficult. The scrupulous use of landmarks should overcome this. The power Doppler quantity obtained by the software is derived from pixel counting and is given in a numbers without units. There may be problems of standardization if different ultrasound equipment is used. It is therefore essential that serial investigations are performed on the same equipment with identical scan settings. A drawback of the present study is that all measurements were made by a single observer. Although intraobserver error was not measured, it was minimized by checking the previous field of view when re-scanning and also by obtaining a mean measurement of three readings. In practice it would seem sensible for a single operator to perform serial studies as fewer variables are introduced into the technique. 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