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- PATIENTS AND METHODS
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- ROLE OF THE STUDY SPONSOR
The accurate assessment of joint inflammation and sensitive monitoring of disease activity in patients with rheumatoid arthritis (RA) is essential in evaluating response to treatment and disease outcome (1). In early RA, synovitis appears to be the primary abnormality responsible for structural joint damage (2). In this case, the monitoring of therapy of patients with RA should focus on synovitis.
It is known that synovial inflammation consists of periarticular vasodilatation followed by synovial proliferation, which is accompanied by angiogenesis resulting in intraarticular blood vessel formation (3). Hypervascularization and angiogenesis of the synovial membrane are considered to be primary pathogenic mechanisms responsible for the invasive behavior of rheumatoid pannus (3–5). Therefore, there is a relationship between joint inflammatory activity and synovial vascularization (6).
Joint synovitis has traditionally been assessed indirectly by means of inflammatory subjective clinical data and laboratory parameters. Imaging techniques such as magnetic resonance imaging (MRI) and musculoskeletal ultrasound (US) are playing an increasingly important role in the evaluation and monitoring of patients with chronic inflammatory arthritis. Assessment of synovial inflammatory activity by MRI has shown a close correlation with histologic findings (7, 8). In addition, MRI findings have demonstrated a predictive value in structural joint damage in early RA (9, 10). However, MRI is expensive, time consuming, and not widely available for routine clinical use in many countries.
The greater resolution of superficial musculoskeletal structures offered by high-frequency transducers has promoted an increasing use of US in rheumatic diseases (11). US is a routinely available, noninvasive, and relatively inexpensive bedside imaging method with high patient acceptability. This technique is more sensitive and reproducible than clinical evaluation in assessing joint inflammation (12–19). The main advantage of US over MRI is that all peripheral joints can be examined as many times as required at the time of consultation, which improves the accuracy of clinical evaluation. In addition, prosthetic joints do not interfere with US images.
Both color Doppler and power Doppler US (PDUS) techniques detect synovial flow, which is a sign of increased synovial vascularization (20). The presence of intraarticular color Doppler/power Doppler signal aids in distinguishing active synovitis from inactive intraarticular thickening (21–29). Color Doppler and power Doppler findings have correlated with local clinical evaluation of joint inflammatory activity (13, 22, 23), overall clinical and biologic inflammatory activity (19), MRI joint inflammatory findings (24, 25, 26), and histologic synovial vascularization (27–29) in patients with RA.
Several studies have demonstrated a significant reduction of joint inflammation evaluated by gray-scale and color Doppler or PDUS in a limited number of arthritic joints in patients treated with different methods (15, 22, 30–37). Nevertheless, to the best of our knowledge, there are no studies on the predictive value of longitudinal US joint assessment in the areas of disease activity, functional status, and radiologic progression in early RA. The purpose of this study was to demonstrate the sensitivity to change of overall PDUS joint assessment and the predictive value of sequential PDUS parameters in clinical, functional, and radiologic outcomes in patients with early RA who started treatment with disease-modifying antirheumatic drugs (DMARDs).
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
- ROLE OF THE STUDY SPONSOR
The development of new reliable methods for assessing synovial inflammation and response to treatment in RA is a challenge in daily practice and clinical trials and a relevant research field in rheumatology. Within the last decade, there has been an increasing use of musculoskeletal US with color Doppler or power Doppler technique for evaluating joint inflammatory activity in patients with RA.
In our study, we chose a combination of gray-scale (presence of joint effusion and/or synovial hypertrophy) and power Doppler findings (presence and grade of intraarticular power Doppler signal) as US variables reflecting active rheumatoid pannus. We found a significant transversal correlation between the PDUS findings and standard measurements of RA inflammatory activity such as the DAS28 and CRP level, whereas correlations between the PDUS parameters and HAQ score were weakly to moderately significant at followup. In a previous cross-sectional study on the comparison of gray-scale and power Doppler US with global clinical and laboratory assessment of joint inflammation in RA, we also found a significant correlation between US parameters and disease activity markers such as swollen joint count, CRP level, and ESR (19). In contrast, there was no correlation between the US variables and HAQ score. This discrepancy may be due to the longest disease duration (mean ± SD 69.3 ± 58.29 months) of the patients included in the previous study. In long-standing RA, HAQ score indicates either disease activity or residual structural joint damage, whereas in early RA, functional status is more likely related to inflammatory activity.
In keeping with our results, other studies have found changes in color Doppler or PDUS to be associated with clinical and laboratory response to intraarticular corticosteroid injections (22, 33, 36), systemic corticosteroid therapy (30, 32), and biologic agents (15, 31, 34, 37) in chronic inflammatory arthritis. However, the sensitivity to change of any method should be demonstrated by calculating the intraobserver variation and the SDD between repeated measurements (50). Most of the previous longitudinal studies have not assessed the sensitivity to change of US parameters. Ribbens et al (15) and Fiocco et al (37) reported intraobserver coefficients of lower variation than the changes in power Doppler findings. We obtained a lower SDD for the US joint count for active synovitis and the US joint index for power Doppler signal than the changes in these variables from baseline to 3 months, 6 months, and 1 year.
Although changes in PDUS parameters and DAS28 score were parallel throughout the study, we did not find a significant correlation between them. Therefore, PDUS findings seem to be a measurement of disease activity independent of standard clinical and laboratory variables.
The active synovitis count and the synovial vascularization index obtained by PDUS demonstrated a stronger correlation with disease activity at the following visit than the clinical, laboratory, and functional parameters, including the DAS28. In addition, the cumulative PDUS parameters of inflammatory activity over time demonstrated a high correlation with disease activity at 1 year and demonstrated the strongest correlation with radiographic damage progression as well as radiographic erosion and total scores after 1 year of DMARD therapy in patients with early RA. Because changes in the RA treatment throughout the study were based only on clinical and laboratory parameters, a predictive value of PDUS findings in disease activity and radiologic outcome may be accepted.
Taylor et al (35) have previously evaluated the prognostic value of US in RA in a recent randomized controlled trial of anti–tumor necrosis factor α in early RA. They demonstrated that the baseline synovial vascularization detected by power Doppler in MCP joints correlated with the radiographic joint damage over the following year (35) in patients receiving only 1 DMARD (methotrexate). In contrast, we did not find a significant correlation between the baseline clinical, laboratory, functional, and PDUS variables and disease activity, functional status, and radiographic damage at 1 year. The different therapeutic regimens prescribed for the patients during the followup may explain the lack of baseline predictors in our study.
The results of both studies can reflect the pathogenic destructive role of angiogenesis in the rheumatoid synovium (3–5). Therefore, the detection of vascularization in early rheumatoid synovial proliferation by PDUS could be considered a strong predictor of disease aggressiveness, which would contribute to making treatment decisions.
Some limitations of our study should be mentioned. First, our study was conducted in accordance with daily clinical practice. Patients were treated with various DMARDs, oral corticosteroids, and NSAIDs at a variable dose during the study. Therapeutic decisions were made without knowledge of US findings. Therefore, we could not compare the predictive value of PDUS variables depending on the DMARD received, evaluate the potential role of different DMARDs in PDUS parameters, or study the effect of PDUS findings in therapeutic decisions.
Moreover, the rheumatologist performing US scanning could not be completely unaware of patient's joint signs and symptoms. To avoid as much bias as possible, US examination was carried out without light so the examiner could not see the joints well, and the patients were asked not to communicate with the US examiner.
The lack of standardization of US examination method and settings for power Doppler can limit the use of this technique in research protocols. Some different methods have been used for assessing color Doppler or power Doppler findings such as semiquantitative signal scoring (15, 22, 30, 36, 37), color pixel counting (31–35), and resistive index calculating (33, 34). We considered semiquantitative signal grading as the most suitable for clinical practice. In agreement with previous studies (15, 37), our intraobserver kappa values and ICCs were very high for PDUS parameters.
In addition, power Doppler is extremely sensitive to tissue movement, especially at low PRF, which can result in flash artifacts. However, we used pulsed Doppler spectra as proof of the presence of vessels when the images were doubtful.
In conclusion, our results suggest that in addition to current clinical and laboratory evaluation, PDUS technique is a sensitive and reliable method for longitudinal assessment of inflammatory activity in patients with early RA in daily management and clinical trials. Furthermore, PDUS inflammatory findings seem to have a predictive value in disease activity as well as radiographic outcome. The latter emphasizes the importance of taking into account PDUS findings for therapeutic decisions in early RA.