Abstract
Objective Ultrasound (US) is increasingly used to evaluate enthesitis. One of the US features of enthesitis is thickening. However, there is no consensus on how the entheseal thickening needs to be defined, and existing cut-off levels have been criticized for being frequently positive in healthy controls (HCs). Our objective was to determine the frequency of thickening of entheses on US using the existing cut-off values in HCs and in patients with axial spondyloarthritis (axSpA) and propose new values to improve discriminative value.
Methods Eighty HCs and 100 patients with axSpA had US scans of 2160 entheses. Sensitivity, specificity, odds ratio (OR), and accuracy were calculated according to accepted cut-off levels from the literature and proposed cut-offs were calculated as the mean ± 2 SD.
Results Thickening according to current cut-off levels was found in 20.4% (196/960) of healthy participants’ entheses and 33% (396/1200) of entheses of patients with axSpA. Thickening according to proposed cut-off levels decreased frequency of thickening in both groups, and therefore increased specificity at the cost of decreasing sensitivity. The only anatomical site where the thickness had a value to discriminate disease from health was seen at the triceps tendon enthesis with an OR of 13.4 (95% CI 4.0-44.8) according to the current cut-offs compared to 10.3 (95% CI 4.0-26.6) with the proposed cut-off levels.
Conclusion Although using cut-offs appears to be an appealing method to evaluate entheseal thickness, the measurements may be affected by several confounding factors, leading to a low discriminative value, except for at the triceps tendon enthesis.
Enthesitis is the inflammation of tendon, ligament, and articular capsule insertions into the bone. The classic assessment for enthesitis is to elicit tenderness at the enthesis on palpation; however, this has poor interobserver reliability.1,2 Therefore, ultrasound (US) is increasingly used to improve the accuracy of entheseal assessment.3-7 Multiple features on US have been used to assess for enthesitis, one of them being entheseal thickening.4 In the absence of histological evidence of thickening, it is an assumption that the interstitial edema in the enthesis leads to thickening, which may also be complicated with fibrosis in the chronic stages. As musculoskeletal US is considered an operator-dependent modality, research has tried to measure entheseal thickening in order to increase its objectivity and reliability. However, it is not clear how the entheseal thickening needs to be defined. Most studies have used standard reference values instead of a subjective judgment for thickening; however, these cut-off values are not well established (ie, not properly tested in healthy people vs patients or have been tested only in a small number of patients).8-12
The objective of this study was to determine the frequency of thickening of entheses on US using current previously published cut-off values in healthy controls (HCs) and in patients with axial spondyloarthritis (axSpA) and determine whether those cut-offs can be improved for their sensitivity and specificity by using newly established cut-off values based on recently published data.13-16 Further assessment analyzed the effect of age, gender, obesity, smoking, and physical activity levels on entheseal thickness.
METHODS
The raw data of 2 previous studies were combined and used for analysis.13,4 Ethics approval was obtained for both studies from the local ethics committee (Ottawa Health Science Network Research Ethics Board 20170660-01H and 20160902-01H). Written consent was obtained with permission to publish the material from both studies. The first study had 80 HCs and 960 entheses, and the second study had 100 patients with axSpA and 1200 entheses. The rheumatological assessment was performed by an experienced rheumatologist (DS) for both studies.
All patients had a US scan by 2 experienced rheumatologists in musculoskeletal US (SB and DS), on the same day of clinical assessment. All scans were performed using a MyLab Twice (Esaote), equipped with a broadband 6-18 MHz linear probe. There was very good agreement between the 2 sonographers (interobserver reliability: intraclass correlation coefficient [ICC] for thickening was 0.94 [95% CI 0.90-0.96]; intraobserver reliability: ICC for thickening was 0.96 (95% CI 0.94-0.99]). Entheseal thickening measurements were made using 34 recorded images. All images were numbered, each having a unique number. Both sonographers were blinded to clinical data and unaware of the results of each other.
The following entheses were included: insertion of triceps tendon to the olecranon process, insertion of quadriceps tendon to patella, origins of the patellar tendon from patella and insertion to the tibial tuberosity, and insertions of Achilles tendon and plantar fascia to calcaneus. The measurements were done by placing the calipers on the tendon margins at the insertion of the deeper tendon margin into the bone, the line being perpendicular to the superficial border of the tendon (Supplementary Figure S1, available with the online version of this article).
Statistical analysis. Data are presented as median, mean, minimum, and maximum values as well as 2 SDs. Group comparisons for US values and frequency of thickening were made using the Mann-Whitney U test or chi-square test, as appropriate. Thickening values under different demographic conditions and physical activity levels within study groups are presented in Supplementary Table S1, available with the online version of this article. The correlation of thickening with age and BMI were evaluated using Pearson correlation analysis (Supplementary Table S2).
Sensitivity, specificity, positive predictive value, negative predictive value, positive and negative likelihood ratios, diagnostic odds ratio (OR), and accuracy were calculated according to (1) current cut-off levels8,15 (Supplementary Table S3, available with the online version of this article) and (2) new cut-off levels calculated as the mean + 2 SD in our healthy group. The method of adding or subtracting 2 SD from the mean provides an interval that is expected to cover 95% of the normal population and is frequently used to calculate cut-off levels in medicine.17 Receiver-operating characteristic (ROC) analysis was used to calculate the area under the ROC curve (AUC). Statistical analysis was performed using SPSS (version 22.0, IBM Corp.).
RESULTS
Baseline characteristics. In the healthy group, 50 of 80 (62.5%) participants were female and the mean (SD) age was 45.0 (16.1). Patients with axSpA were more frequently male (62%), but the mean (SD) age was 45.3 (13.7) and therefore comparable (Supplementary Table S4, available with the online version of this article). The mean (SD) thicknesses of the scanned sites and the proposed cut-offs using the mean ± 2 SD in our healthy group are given in Table 1 and Table 2, as well as in Supplementary Figure S2.
Entheseal thickening in each site within study groups.
Performance of current and new entheseal thickening cut-off values.
Frequency of thickening using the current cut-off values based on anatomical sites. Thickening according to the current cut-off levels was found in 86.3% (69/80) of the healthy participants, in 20.4% (196/960) of the entheses. It was most commonly seen on the proximal patellar tendon origins (56%) and insertions (31%; Supplementary Figure S3, available with the online version of this article). Thickening according to the current cut-off levels was found in 84% (84/100) of patients with axSpA, in 33% (396/1200) of the entheses. Using the same cut-off values, patients with axSpA also had thickening at the same sites more often (patellar tendon origins [67.5%] and insertions [52%]). The other anatomical sites had less frequent thickening using the current cut-off levels, being slightly more frequent in patients with axSpA than in healthy controls (HCs; Supplementary Figure S3).
Frequency of thickening using the proposed cut-off values based on anatomical sites. Thickening according to the proposed cut-off levels decreased the frequency of thickening in HCs to 17.5% (14/80 of the controls) and to 4.7% (45/960) of entheses, and in patients with axSpA to 41% (41/100 of the patients) and 9.2% (111/1200) of the entheses. For individual anatomical sites, thickening was seen between 3.1% to 6.9% for HCs, and 3% to 25% for patients with axSpA (Supplementary Figure S3, available with the online version of this article).
Performance of entheseal thickening to discriminate disease from health. For current cut-offs, the best sensitivity and specificity were found at the triceps tendon level, whereas the thickening at the proximal and distal patellar tendon origins had the worst sensitivity and specificity (Table 2). The new proposed cut-off levels increased the specificity in all anatomical areas, but at the cost of decreasing sensitivity, except for at the triceps tendon.
Overall, the only anatomical site where the thickness had a value to discriminate disease from health was seen at the triceps tendon, with an OR of 13.4 (95% CI 4.0-44.8) according to the current cut-offs and 10.3 (95% CI 4.0-26.6) with the proposed cut-off levels. Triceps tendon thickening had higher and significantly better AUC value on the ROC analysis to discriminate axSpA (Figure; Supplementary Table S5, available with the online version of this article). None of the other anatomical sites were able to discriminate both groups, using either of the cut-offs.
ROC curve for identifying optimal entheseal thickening, which can discriminate axSpA at each site. AUC values were given with CI per site. AT: Achilles tendon; AUC: area under curve; DP: distal patellar tendon; PF: plantar fascia; PP: proximal patellar tendon; QT: quadriceps tendon; ROC: receiver-operating characteristic; TT: triceps tendon.
Factors contributing to the thicknesses. Men had higher thicknesses at all entheseal sites, in both HCs and subjects with axSpA (Supplementary Table S1 and Figure S4-S5, available with the online version of this article). Similarly, subjects who were overweight or obese had higher values than those with a low BMI. There was no statistical difference according to physical activity in HCs (Supplementary Table S1).
Age had inconsistent effects on thickness. In HCs, age was an important factor to increase the thicknesses, other than thickening at origins and insertions of patellar tendon. This was different from patients with axSpA, where thicknesses increased with age only at the level of the plantar fascia, and not at any other anatomical sites (r = 0.16, P = 0.02; Supplementary Table S5).
Smoking also had variable effects on thickness, in that it increased thickness at the triceps and quadriceps (Supplementary Table S1, available with the online version of this article).
DISCUSSION
There are several different ways to define entheseal thickening. The first is to compare the body of the tendon to the tendon insertion into the bone7 and the second is to compare a side of interest to a normal contralateral entheseal insertion. The third method is to use cut-off values to differentiate between health and disease. Although the first 2 ways can be used to define entheseal thickening, the theoretical advantage of using cut-off levels is that it allows for standardization and reproducibility for being more objective. However, there are major concerns with the current existing cut-off levels. Standard reference values for entheseal thickness have not been well established in HCs. The numbers used in the literature were either derived from trials with very small sample sizes or the measurements were made from the inappropriate sites. For example, the cut-off values for the thickness of the Achilles tendon are based on the study by Olivieri et al,9 which included 14 patients (there was no separate true HC population) by using 9 nontender sites on the same patients as their controls. Similarly, for the patellar tendon, reference values were determined based on 11 cadaveric samples, with the thickness measurement being determined at the midway point between the inferior pole of the patella and tibial tubercle,10 which would be distant to the entheses.
Using these existing cut-off levels, studies including HCs demonstrated frequent thickening in multiple entheses.13 Especially when seen in the absence of any other structural lesion, thickening may be seen as a response to factors such as older age, higher BMI, physical activity, and gender. To overcome this, we tested new cut-off levels. The new cut-off levels are higher than previously defined cut-off levels, which led to increased specificity however at the cost of decreased sensitivity.
A limitation of our study is that we took into account only factors we know affect thickening. However, there are many more factors important to thickening that we do not yet know about and therefore were not included in our study. Another limitation is that data on race were not included in our study. Additionally, although much larger than in previous publications, our sample size was small, and therefore may have limited our ability to redefine thickness cut-off levels and study the influence of the variables in question. In addition, some variables were different across controls, such as gender and BMI, which may have influenced our results. Of our HC group 17.7% were classified as being obese, which would not be considered as truly being healthy (Supplementary Table S2, available with the online version of this article). However, if we had chosen to select participants with certain BMIs, it would have affected the generalizability of our results. The small sample size and the distribution of the thickness values did not allow for an analysis of the interaction between these potential variables. Further, our purpose was only to test the cut-off values and not compare different methods of assessment of thickening. Subjective assessment of thickening was not performed; therefore, we were not able to assess whether one method is more accurate than the other.
In conclusion, although using cut-offs appears to be an appealing method to evaluate entheseal thickness, the measurements may be affected by several confounding factors, leading to a low discriminative value. The newly tested cut-off levels did not improve the discrimination disease from health, in comparison to the previous cut-off levels. Entheseal thickness may still be of value; however, instead of doing an actual measurement, comparing with the contralateral side may be more useful. When it comes to methods used to assess for enthesitis, it may be more objective to look for other methods including structural changes, Doppler US, or hypoechogenicity,18 which was not the purpose of the current study. Further, newly tested cut-off values did not provide improvement of existing thresholds.
Footnotes
DS received funding from UCB through an axial spondyloarthritis fellowship. SB received funding from The Scientific and Technological Research Council of Turkey and the Turkish Society for Rheumatology. The authors declare they have no support in the form of industrial support relevant to this study.
The authors declare no conflicts of interest relevant to this article.
- Accepted for publication June 22, 2022.
- Copyright © 2023 by the Journal of Rheumatology
