The US variables of joints and tendon synovial sheaths were compared between the SNRA group and the OA group. It was found that the detection rate of abnormal US variables of joints and tendon synovial sheaths and the total scores of US variables in the SNRA group were higher than those in the OA group. The two groups were significantly different in the distribution of the grade of US variables. The total scores of most US variables in the SNRA group were positively correlated with CRP, ESR and DAS28. However, no such correlations were observed in the OA group. Moreover, the total scores of US variables had a high diagnostic value for SNRA. Among the variables, the total PD score of joints had the highest diagnostic value for SNRA,and the corresponding the cut-off value was 4. HFUS was used to assess joints and tendon synovial sheaths, which facilitated the differential diagnosis of SNRA and OA and the clinical diagnosis of SNRA.
RA is a chronic, autoimmune disease primarily involving the joints, which is featured by persistent synovitis and may cause cartilage and bone injury and deformity of multiple joints. Early diagnosis and treatment are critical for RA. Several autospecific antibodies are usually available in the serum of RA patients. Among them, RF and ACPA are indicative factors for the diagnosis of RA . At present, SNRA refers to RA with negative serological results for RF and ACPA although the patients conform to the 2010 ACR/EULAR diagnostic criteria. SNRA accounts for 10–30% of all RA patients. However, there are controversies about SNRA, and it may be wrong to consider SNRA as a mild type of RA. Both SNRA and OA are more common in the middle-aged and elderly. SNRA is featured by invasiveness of RA and the serologically occult nature of OA. It is sometimes difficult to differentiate SNRA from OA based on clinical manifestations alone. SNRA is very likely to be misdiagnosed as OA. Usually, a long observation window is required before confirmed diagnosis of SNRA. For this reason, it is difficult to identify and manage SNRA at an early stage[1,24−25]. Radiological imaging is also significant for the diagnosis of SNRA apart from clinical symptoms and laboratory tests.
With a high-frequency probe, the diagnostic value of US in synovitis, tenosynovitis, and BE is not less than MRI[4, 9]. US is also known for its high intra-rater and inter-rater reliability [7, 10]. Given all these features, US is a good choice for early diagnosis of SNRA, which differentiates SNRA from OA. GS ultrasound allows direct visualizing of the morphology and quantity (hypertrophy) of the synovial tissue.PD ultrasound can be used to visualize blood flow in joints and tendon synovial sheaths, with a high sensitivity and specificity for inflammation[8, 12]. In the present study, the detection rate of abnormal joints upon GS and PD and the total GS score of joints and the total PD score of joints in the SNRA group were also higher than those of the OA group, respectively.Although the number of joints with GS grade 2 and PD grade 2 was larger in both groups, the average GS score of joints and the average PD score of joints in the SNRA group were higher than those of the OA group. Besides, the two groups were significantly different in the distribution of the GS and PD grade. The diagnostic value of total GS scores of joints and total PD scores of joints was higher for SNRA (AUC > 0.85). The diagnostic value of total PD scores of joints was the highest, and the corresponding the cut-off value was 4. Thus, blood flow signals detected by PD in at least two involved joints with a cumulative score of 4 indicated SNRA. GS and PD ultrasound of joints in the two groups was helpful for differential diagnosis of SNRA and OA.
BE is a primary feature of RA, which has been widely recognized for its role in the pathogenesis, disease, and prognosis of RA. BE is a joint injury in RA, and closely related to irreversible joint function loss. Early diagnosis of RA is important for disease management and prevention of further joint injury[28–29]. HFUS usually reveals locally unsmooth cortex of the articular surface, with disrupted continuity and eroded edge, or even extensive cystic deformation on the bone surface, which may evolve into a bone cyst. HFUS and MRI were similar in detecting early, small erosions on the cortex surface [9, 30]. Kosta et al.  reported BE upon MRI in 96.2% of the RA patients with a course shorter than 3 months. Ji et al.  found BE by ultrasound in 44.8% of the RA patients with a course shorter than 2 years. Besides, the number of joints with BE was much larger in RA patients than in non-RA patients. Compared with the OA group,the detection rate of BE ,the total BE score, grade of BE, and the average score of BE were higher in the SNRA. The diagnostic value of total BE scores was also high for SNRA (AUC > 0.85). Among the total scores of five US variables, the specificity of the total BE score was the highest, which was 95.00%, but the sensitivity was poor. Severe BE was already indicated upon the initial visit in some SNRA patients (about 9.28%). In fact, these patients were not diagnosed at an early stage. However, due to poor medical compliance and non-standard early treatment, some patients with joint pain as the primary clinical manifestation are not covered by the diagnostic and therapeutic guidelines, which may lead to delayed treatment. Given the facts above, early diagnosis and treatment of SNRA are equally important as other types of RA patients.
Tenosynovitis is an early manifestation of RA and also a critical cause for functional disability , which may also be a good radiological indicator predicting early development [3, 34]. However, tenosynovitis usually presents with joint swelling and pain with poor specificity, which is not easily differentiated from other etiologies and is usually neglected in clinical practice , and there are limited data about its prevalence. Given the facts above, the early diagnosis of active tenosynovitis is particularly important. The diagnosis of this disorder can be helpful to improve new classification criteria,and also prevent the development of damage [9,36−37].In the present study, the detection rate of affected tendon synovial sheaths upon GS and PD was 39.06% and 30.87% in the SNRA group, respectively, which were higher than 7.71% and 0.94% in the OA group, respectively. Compared with the OA group, total GS scores of tendon synovial sheaths, total PD scores of tendon synovial sheaths, GS scores of tendon synovial sheaths, and average scores were higher in the SNRA group. In the OA group, tenosynovitis with GS grade I was dominant, and there were 68 such affected tendon synovial sheaths (91.89%). No patients positive for tenosynovitis upon PD were detected in the OA group. It was probably because GS-indicated tenosynovitis was not at the active stage in the OA group. The total GS score of tendon synovial sheaths and the total PD score of tendon synovial sheaths were also of a high diagnostic value for SNRA (AUC > 0.85). The finding of tenosynovitis facilitated early diagnosis of SNRA.
Clinically, CRP, ESR and DAS28 are considered indicators for RA activity. DAS28 is an essential indicator of RA activity, but its calculation is more complicated. In addition, ultrasound may still uncover subclinical inflammatory changes of patients in the remission stage of DAS28-defined RA . Synovial inflammation indicates systemic inflammatory response, which is featured by increased serum CRP levels. Therefore, serum CRP levels are proven to be an indicator of synovial inflammation and related to radiological progression. CRP and ESR are the most common laboratory indicators of inflammatory activities, but they are vulnerable to disturbance from other factors, such as infection. In the present study, CRP, ESR and DAS28 in the SNRA group were higher than those in the OA group, indicating that most SNRA patients were at the active stage of inflammation. Meanwhile, except for CRP, which was not correlated with the total BE score in the SNRA group, total GS scores of joints, total PD scores of joints, total BE scores, total GS scores of tendon synovial sheaths, and total PD scores of tendon synovial sheaths were positively correlated with ESR, CRP, and DAS2. The reason may be that BE of joints is a chronic process and may be asynchronous with disease activity. Moreover, serum CRP is prone to be influenced by other factors, such as infection. The correlation between CRP and total BE scores may be further investigated by increasing the sample size. In the SNRA group, ultrasound findings of joints and tendon synovial sheaths were consistent with disease activity, demonstrating that ultrasound is potentially used to assess disease activity.
There are some limitations in the study. First, it was a retrospective single-center study, and the sample size was small, especially the number of OA patients. Second, Of note, the ultrasound scoring systems for joints and tendon synovial sheaths were not designed for OA and did not assess for typical OA features (joint space narrowing, osteophytes). Hence, more informative ultrasound assessment systems should be used in future prospective studies to assess the differences between SNRA and OA patients.Third,All ultrasound evaluations are taken by the same physician, which may be biased and affect the results. Last, only 22 joints and 24 tendon synovial sheaths of the two hands were examined in the two groups. Distal interphalangeal and Carpometacarpal joints those were prone to OA were not included.What’s more,the diagnostic efficacy of HFUS for joints in other parts of the body remains to be investigated in the future.
In conlusion, HFUS facilitates differential diagnosis of SNRA and OA and the clinical diagnosis of SNRA through assessment of joints and tendon synovial sheaths.