Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by joint swelling, joint tenderness, and destruction of synovial joints, leading to severe disability and premature death (1, 2). Over the last decade, the use of disease-modifying antirheumatic drugs, in particular, methotrexate (MTX) and biologic agents, has been shown to improve the clinical outcome of RA, especially when the treatment is implemented at an early stage, before joint damage accumulates (3).
The new classification criteria for RA were developed and published in 2010 by the joint working group of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) (4–6). To identify patients who would benefit from early effective intervention, factors associated with the subsequent decision by a physician to start MTX treatment within a year after presentation were extracted from cohorts of real-world patients with early arthritis (5). As a result, the final criteria consist of clinical and laboratory features characteristic of early RA and enable rheumatologists to classify a patient with early RA without typical radiographic changes much easier than by using the 1987 revised ACR criteria (7). However, the accuracy of the new criteria for identifying patients with a disease that required MTX treatment was not consistently very high among the cohorts used for validation (area under the curve [AUC] 0.66–0.82 for receiver operating characteristic [ROC] curve analysis). One possible reason for this varying accuracy of the criteria is poor reproducibility of clinical joint examination findings (i.e., swelling and tenderness) (8–10).
Ultrasound assessment is more sensitive than clinical joint examination in detecting inflammation in synovial tissues (8, 11–13). In fact, the 2010 ACR/EULAR criteria refer to a possible use of imaging techniques such as ultrasound “for confirmation of the clinical findings” (4). However, there have been no reports of validated methodology for translating ultrasound findings of synovitis on gray-scale (GS) images and power Doppler (PD) signal in the synovium into a dichotomous variable for the presence of synovitis. This study aimed to determine the optimized definition of synovitis findings on ultrasound for the 2010 ACR/EULAR criteria and to assess the impact of its use on the accuracy of RA classification.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
- Supporting Information
In the present study, we showed that confirming the presence of synovitis with ultrasound changed not only the prevalence of synovitis at the joint level, but also the fulfillment of the 2010 ACR/EULAR RA classification criteria in a certain proportion of patients. Furthermore, we demonstrated that criteria based on ultrasound findings may classify more accurately patients who subsequently require MTX treatment than do criteria not based on ultrasound findings. In our study, 2 provisional definitions of ultrasound-detected synovitis provided either superior sensitivity or superior specificity when used in the 2010 ACR/EULAR criteria.
The 2010 ACR/EULAR criteria, which were developed by the joint working group through a data-driven approach followed by consensus methodology, underscore the importance of synovitis, requiring at least 1 clinically swollen joint and giving the highest weight to the joint involvement (4). However, joint involvement is the most skill-dependent and irreproducible domain as compared with others, especially when joint manifestation is modest. The results of our study, which used the same gold standard that was used in the development of the original criteria, indicate that the presence of mild synovitis on GS imaging could be used to confirm the presence of synovitis for improved sensitivity of RA classification; further, the presence of moderate (but not mild) synovitis on GS imaging or abnormal synovial PD signals could be used for improved specificity. Given that rheumatologists who made the clinical decision to prescribe MTX already knew the 2010 ACR/EULAR criteria and had access to all clinical data except ultrasound findings, the superiority of ultrasound-detected synovitis over clinically detected synovitis in predicting the requirement for MTX treatment is significant.
One important finding of our study is that ultrasound is not only very sensitive for detecting synovitis, which has been demonstrated by a number of studies (8, 11, 12), but it also provides very specific assessment of synovitis as compared to clinical joint examination and can therefore exclude false-positive results, both at the joint level and at the level of the whole patient. A certain proportion of joints with apparent swelling or tenderness did not have any ultrasound-detected synovitis, depending on the joint (5.8–10.9%) (Figure 1B). Furthermore, a certain proportion of patients who fulfilled the 2010 ACR/EULAR criteria were reclassified as not having RA according to ultrasound detection of synovitis (6.4–15.6%) (Table 3), and these patients were less likely to develop disease requiring MTX treatment, even though the ultrasound information was not available to the rheumatologists (Figures 2B and C). These data suggest that joints with clinical synovitis alone are frequently false positive, and patients who fulfill the criteria with only those false-positive joints do not necessarily need immediate MTX treatment.
Filer et al (21) performed comprehensive ultrasound assessment in 58 patients with very early arthritis and showed that the ultrasound joint count (GS score ≥1) was greater than the clinical joint count in every joint region and that the ultrasound joint count improved the sensitivity of the 2010 ACR/EULAR criteria for predicting development of RA at the cost of specificity. In addition, they demonstrated by regression analysis that involvement of wrist and MCP joints on GS imaging and synovial PD signal involvement of metatarsophalangeal joints provided independent information predictive of RA development.
Although their study and ours have some results in common, there are 2 major differences. First, we considered the 2010 ACR/EULAR criteria as the most established criteria at the moment and aimed to incorporate ultrasound assessment into the criteria, whereas Filer et al (21) determined the ultrasound components that correlated with subsequent fulfillment of the 1987 revised ACR criteria, using the 2010 ACR/EULAR criteria as one model for comparison. Second, the study subjects were different. While they studied patients with symptoms lasting ≤3 months, we included patients with symptom duration up to 3 years, which was the same criterion used in the data-driven process for developing the 2010 ACR/EULAR criteria. However, we did not exclude patients with no swollen joints at presentation based on the hypothesis that such patients could also have significant synovitis that is detected only by ultrasound. Indeed, the hypothesis was correct, as we actually identified 10 patients with ultrasound-detected synovitis without any swollen joints who subsequently developed disease requiring MTX treatment. These differences in the purpose and the study subjects may account for the difference between the 2 studies in the prevalence of ultrasound-detected synovitis for each joint and in its relative importance.
Although the 2010 ACR/EULAR RA classification criteria were not meant to be “diagnostic criteria,” they have already been used as a diagnostic aid in daily rheumatology practice. Ultrasound has also been used in rheumatology practice, and the benefit of ultrasound assessment combined with the well-accepted criteria is clinically relevant. Nevertheless, although we demonstrated that confirming synovitis with ultrasound is preferentially beneficial in equivocal cases, a comprehensive ultrasound scan of 38 joints in those cases is still time-consuming and not necessarily cost-effective in daily practice. To improve the feasibility of ultrasound-assisted diagnosis, the number of joints needs to be reduced. Thus, identifying the optimal core set of joints with a high predictive value can be the next agenda. However, such analyses to identify every clinically important joint require a much larger sample size than ours, because regional distribution of synovial inflammation is highly variable among patients. Another possible strategy to reduce the number of joints is to scan joints only when the clinical findings are equivocal.
The major limitation of our study is that it was a single-center study with a small sample size. Compared with the early arthritis cohorts used in the data analysis for the 2010 ACR/EULAR criteria (5), a larger proportion of our study cohort were female (78.0% versus 66.8%), mean swollen and tender joint counts were lower (3.3 versus 6.6 and 3.3 versus 8.0, respectively), markers of inflammation were less elevated (mean erythrocyte sedimentation rate 22 mm/hour versus 32 mm/hour and mean C-reactive protein level 0.9 mg/dl versus 2.6 mg/dl), and the mean duration of arthritis symptoms was longer (8.4 months versus 4.9 months). However, most of the means of these variables were within the range of variation among the cohorts used in the phase I process for the 2010 ACR/EULAR criteria (5). The sample size of our study was large enough to validate the additional benefit of ultrasound in the 2010 ACR/EULAR criteria, but a larger number of patients would have allowed more accurate assessment of the less prevalent pathology (e.g., PD score ≥2) and of the joints less frequently involved at an early stage (e.g., shoulder).
Another limitation is the validity and generalizability of the ultrasound method used in our study. Although standardized grading methods and standardized synovial sites and joints for global assessment have not yet been reported, results of a study using such standardized methods in the future will be more readily generalizable. Taken together, a global, multicenter study that uses standardized methods for ultrasound evaluation is warranted to provide a feasible, cost-effective, and validated ultrasound methodology to confirm the presence of synovitis for the 2010 ACR/EULAR RA classification criteria. Our data present a rationale for such a large-scale study and provide preliminary but vital information for the possible definitions of ultrasound-detected synovitis and the possible target population.
- Top of page
- PATIENTS AND METHODS
- AUTHOR CONTRIBUTIONS
- Supporting Information
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Ikeda had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Ikeda.
Acquisition of data. Nakagomi, Ikeda, Okubo, Iwamoto, Sanayama, Takahashi, Takatori, Suzuki, Takabayashi, Nakajima.
Analysis and interpretation of data. Nakagomi, Ikeda, Yamagata.