The Role of Bone Scintigraphy in the Diagnosis of Rheumatoid Arthritis According to the 2010 ACR/EULAR Classification Criteria

Early diagnosis of rheumatoid arthritis (RA) is crucial because increasing evidence suggests that prompt treatment leads to a better outcome and prognosis (1-3). The results of these studies has recently led to the development of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria, a new approach to classifying RA and initiating treatment at an earlier stage (4).

Unlike the 1987 ACR criteria, the presence of rheumatoid nodules and typical changes on X-rays, which both reflect long-standing disease, are not included in the new criteria, although serological markers and acute phase reactants are now included. Regarding joint involvement, ambiguous judgment of symmetric distribution and involvement of three or more joints are no longer necessary data points, whereas the number and sites of joint involvement with clinical evidence of synovitis have decisive influence on the diagnosis according to the new criteria (4). However, it is not easy to assess whole body joint swelling and tenderness during a short interview, and the possibility of over- or underestimating the extent of joint involvement always exists since detection during the physical examination depends on patient complaints of joint symptoms. Furthermore, some patients may have already taken anti-inflammatory agents before seeing their rheumatologists, which can make it difficult to observe active arthritis on physical examination. In these circumstances, the diagnosis will require some imaging modality to provide more objective information to complement the clinical assessment.

Bone scintigraphy (BS) that utilizes Tc-99m phosphonate compounds has high sensitivity but low specificity for the detection of bone and joint disease. In other words, using this test, we can easily identify active arthritis in patients, although the results are not specific for RA. For many years, the importance of BS for measuring joint inflammation in RA patients has been emphasized (5, 6). Several previous studies have also confirmed that BS has a high rate of clinical utility in rheumatology (7). Moreover, increased blood pool activity of the involved joints on BS correlated with inflammatory synovitis, which is an early sign of RA (8). Hence, we thought that BS, especially in the blood pool phase, might be useful in suggesting early joint involvement in RA and would be even more meaningful when applied using the new 2010 criteria.

In the current study, we evaluated how BS could supplement the 2010 criteria in the diagnosis of RA during the initial work-up of patients with joint symptoms.

Our results indicate that the BS only or BS-assisted diagnosis did not show a noticeable increase in sensitivity in the evaluation of patients with arthritis compared to the 2010 criteria assessed by physicians only. However, in patients without arthritis who were not eligible according to the 2010 criteria, BS-assisted diagnosis can help to detect RA with high PPV. The AUC of the ROC curve showed better discrimination of true RA patients in BS-assisted diagnosis than using the 2010 criteria assessed by the physician only in both groups (with or without arthritis at the initial physical examination). Moreover, among patients with arthritis who did not satisfy the 2010 classification criteria (score<6), BS assisted diagnosis identified additional true RA patients with high PPV, which could be valuable support in daily clinical practice. Therefore, BS-assisted diagnosis seems to be helpful in the diagnosis of RA among patients who do not satisfy the 2010 criteria (score<6) as well as suspect patients who are ineligible for the 2010 criteria due to dubitable arthritis at clinical presentation.

To keep pace with the new paradigm for early diagnosis and management of RA, there is also a need for more sensitive imaging modalities that can allow clinicians to carefully track the development of early joint inflammation and damage. Several other modalities have also been studied for the efficacy of evaluating early changes in RA but require further development. Ultrasonography (US) is primarily designed to depict synovial inflammation rather than to directly assess bone destruction (8); it has intra- and interobserver reliability of measures (9) but lacks standardization. Magnetic resonance imaging (MRI) can also be used to detect inflammation outside (synovitis) and inside (osteitis/bone marrow edema) the cortical bone lining, as well as bone edema and erosions (10, 11), but it is expensive and has limited performance regarding all joints of interest.

However, BS has several advantages over the aforementioned modalities, which are high sensitivity, good availability, low cost, and ability to image the entire body (12). The latter seems most important in RA patients where whole body imaging makes it possible to show widespread joint involvement. BS is a highly sensitive technique that has been used in the diagnosis and management of skeletal pathology for nearly 3 decades (13). In contrast, our results of "BS only" diagnosis have relatively low sensitivity. This discrepancy probably occurred because we defined RA not when increased radiotracer uptake was seen on the "blood pool phase" and/or the "bone phase" but only when the uptake was corresponding to the predilection site of the joint involvement of RA. Because ^99mTc-HDP binding depends on the osteoblast activity and on the bone remodeling rate, it is not specific for a particular disease process (12). Fisher et al. (14) also argued about the lack of specificity of BS and their minor role in the evaluation of polyarthralgia. In that respect, single photon emission computed tomography/computed tomography (SPECT/CT), a type of the hybrid imaging modalities combining a high-resolution structural image and a functional radionuclide scan image, might improve the specificity through accurate localization of the foci of abnormal uptake and additional structural information (12). However, further studies are required for the exact impact of SPECT/CT compared to planar BS, and SPECT/CT currently has limited accessibility in many facilities. Therefore, our current study using planar BS in the evaluation of RA patients is still significant.

In a real practice setting, however, BS itself cannot be a diagnostic tool for RA because rheumatologists make clinical decisions using a combination of clinical experience, diagnostic criteria, laboratory results, and imaging findings for the gold standard diagnosis of RA. In other words, it is impossible to judge the absolute role of BS alone in the diagnosis of RA. Therefore, we evaluated the diagnostic value of BS as a supplemental tool to the 2010 ACR/EULAR classification criteria ("BS assisted" diagnosis). In this instance, BS was used as an objective indicator of joint involvement during evaluation of the 2010 criteria to replace the subjective measure of physician judgment.

The sensitivity and specificity of the 2010 criteria have been reported to range between 62%-74% and 71.4%-78%, respectively (15-17). The sensitivity values of our 2010 criteria assessed by physician only and by physician with BS assistance were comparable or even slightly higher than those obtained in other studies. Here, our specificity value was much higher than previous studies. The reason for this high specificity was that all the patients were enrolled from our tertiary academic rheumatology department and were assessed by rheumatologic experts. Therefore, the proportion of RA patients as well as non-RA patients with clear-cut clinical manifestations was relatively high, and the patients with undifferentiated arthritis who could be confused with RA was relatively low.

This study has a limitation. We restricted this study to patients who visited our clinic with joint symptoms and for whom laboratory and BS data were available. Therefore, the prevalence for RA might be higher than in the general population. In other words, the diagnostic validity of the 2010 criteria with or without BS assistance might be lower in the general population. However, a benefit is that this type of selection criteria reflects cases encountered in a real practice setting. Therefore, additional investigation is needed to assess which subgroup and clinical setting will allow the 2010 ACR/EULAR classification criteria, assisted by BS, to have better cost-effectiveness and diagnostic performance.

In conclusion, the diagnostic validity of BS-assisted diagnosis of RA on the basis of the 2010 ACR/EULAR classification criteria seems to be comparable to the diagnosis of physicians only for patients with arthritis. Moreover, it can provide valuable information about the number and location of whole body joint involvement, especially for patients who do not satisfy 2010 criteria as well as those who are ineligible for the 2010 criteria due to dubitable arthritis upon initial work-up.