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We read with interest the paper by Carotti et al that appeared in the October issue of the Annals of the Rheumatic Diseases.1 The authors investigated the usefulness of contrast enhanced power Doppler ultrasonography (PDS) in determining the vascularisation rate of the synovial pannus of patients with rheumatoid arthritis (RA). After intravenous infusion of an echo contrast (Levovist, Schering, Germany) PDS was performed on the knee joints of 42 patients with RA, who had previously been classified as having active (n=15), moderately active (n=14), and inactive knee synovitis (n=13). The results were expressed as the area underlying time-intensity curves. Highest vascularisation scores were found in patients with active synovitis (216.2 (33.4), mean (SD)), whereas lower values were found in those with moderately active (186.8 (25.8)) and inactive synovitis (169.6 (20.6)). Significant difference (p<0.01) was found between the active and the inactive group only. Also, significant correlations were found between the vascularisation scores and some indices of the disease activity. The authors concluded that PDS may be a valuable method of distinguishing between inflammatory and non-inflammatory pannus of knee joints in RA and thus may have a clinical potential for both diagnostic and therapeutic purposes.
Unfortunately, Carotti et al did not provide any data on the sensitivity and specificity of the method used. Moreover, no figure showing distribution of the vascularisation scores in individual patients and/or confidence limits of the mean was available. This is a major problem and, in our opinion, the data presentation does not allow for any conclusions about how the PDS really performs in clinical settings. It should be emphasised that statistical significance alone is not sufficient as it could easily be achieved if there were some lower and some higher vascularisation scores in patients with inactive and active synovitis, respectively.
We are aware that the study was designed as a preliminary one and a relatively small group of patients was included. Nevertheless, we believe that all Annals readers would benefit much from seeing the sensitivity and specificity figures/estimates or the presentation of the individual vascularisation scores. We wonder if these could be provided by the authors.
The statement that ultrasonography offers a simple, non-invasive, reproducible, non-radiating, and inexpensive imaging technique was made several times in the paper. It holds true for ultrasonography as a general imaging technique. However, it seems somewhat misleading in the context of the methodology used by the authors. PDS is not a simple technique as it requires a team of well trained and experienced radiologists and technicians who are aware of possible caveats of the method. The procedure requires venepuncture and an intravenous contrast infusion, and thus can at most be regarded as a low invasive one. It should be emphasised that Levovist, although generally well tolerated, may rarely lead to some adverse reactions (for example, local tissue irritations, dyspnoea, changes in pulse/blood pressure, nausea, vomiting, headaches, dizziness, skin reactions—data taken from the compound data sheet). To our knowledge, no data exist on the reproducibility of PDS for the knee pannus examination. A high-end equipment has to be used to achieve good results which is relatively expensive. It seems that from the long list of adjectives used by the authors, “non-radiating” is the only valid one for the PDS method described.
We thank Drs Hrycaj and Lacki very much for their comments because they give us the opportunity to illustrate further details of our study.1 Recent papers have shown a very close relationship between the results of power Doppler sonography (PDS) and those of dynamic gadolinium (Gd) enhanced magnetic resonance imaging (MRI; a sensitivity of 88.8% and a specificity of 97.9%),2 and between PDS findings and histopathological findings3 of synovial membrane vascularity. It has also been shown that contrast enhanced PDS significantly improves the detection of intra-articular vascularisation, compared with the unenhanced technique.4 Contrast enhanced PDS demonstrated significant difference in intra-articular colour flow signals between joints of patients with inactive RA and those with active RA, between joints of patients with inactive RA and those with moderately active RA, and between joints of patients with moderately active RA and those with active RA.5
With regard to the sensitivity and specificity of the PDS technique, as far as we know no data have been reported. Our study has all the features of a preliminary investigation and, obviously, cannot answer all the questions on the topic. However, the receiver operating characteristic (ROC) curve was employed to describe how well various values of the area underlying the enhancement curves of the PDS can detect patients with RA with high and low synovitis activity (fig 1).6 This analysis involves plotting the true positive rate (sensitivity) against the false positive rate (100 − specificity) for possible cut off scores. Sensitivity and specificity (which constitute the discriminating ability of a test) were used in agreement with the current definitions of these terms.7 Moreover, we calculated 95% confidence intervals (CI) of sensitivity and specificity. Each point on the ROC plot represents a sensitivity/specificity pair corresponding to a particular decision threshold.8,9 The area under the ROC curve is used to evaluate the screening scale’s performance. For PDS, the mean (SEM) area under the curve is 0.859 (0.072); 95% CI 0.675 to 0.960. According to Swets et al, areas from 0.50 to about 0.70 represent poor accuracy, those from 0.70 to 0.90 are “useful for some purposes”, and higher values represent high accuracy.7 From the ROC curve in fig 1 we computed the optimal cut off point, corresponding to the maximum sum of sensitivity and specificity. For our method an optimal point of 191 comes close to maximising both sensitivity and specificity. With this cut off point for the area under the time-intensity curve, the sensitivity is 80.0% and specificity is 84.6%. These findings have implications for both clinical practice and research purposes in assessment of disease activity in patients with RA.
Figure 2 shows the distribution of PDS scores in individual patients with active and inactive synovitis and the confidence limits of the mean. The mean (SD) values of the areas under the curves showed a significant difference (p<0.01) between the patients with active synovitis (216.2 (33.4); 95% CI 193.1 to 239.4) and those with inactive synovitis (169.6 (20.6); 95% CI 150.8 to 188.4) (fig 2).
The characteristics of PDS are no more complex than those of many other clinical or instrumental procedures commonly used in daily clinical practice. It obviously requires adequate training and high quality equipment. In our study all the investigations were performed by one of the authors (MC), who is specialist both in rheumatology and radiology. As with all drugs, echo contrast agents may have side effects, although most of the side effects have been reported to be mild and not prolonged. In our patients no clinical side effects from the agents were detected. We excluded from the study patients with galactosaemia, with suspected pregnancy and critical illness and patients who had taken any contrast agent within 24 hours.
We agree with Drs Hrycaj and Lacki that the use of echo contrast agents is, at this time, relatively expensive, and they are not yet routinely available, but it may be a cost effective alternative to dynamic MRI. Moreover, the implementation of microinjection devices that are currently being studied may decrease the required dose of contrast medium, and this should reduce overall examination time and the cost of ultrasound contrast agent for each patient. Consequently, the cost of contrast enhanced PDS should be comparable with that of other techniques. The assessment of reproducibility is a problem of all diagnostic procedures based on the use of contrast agents for obvious ethical reasons. This and other complex aspects of a new methodological approach to the study of rheumatoid synovitis cannot be extensively examined in a single preliminary report.
Although PDS with contrast agents has some well known limitations, it allows access to otherwise undetectable information that may improve our basic knowledge of rheumatoid synovitis and, in the near future, might also be useful in the assessment of disease activity in RA.5
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